Second line Bladder Cancer Therapies When First Line Treatments Fail

we'll talk about second line bladder cancer therapies when first-line treatments fail and for the purposes of this you know our bladder cancer session is going a little bit from non muscle invasive to muscle invasive so we're gonna hang out with non-muslim base of disease for the most part I have no disclosures for this topic so in the non muscle invasive bladder cancer world that consists of clinical ta clinical t1 and then clinical T is your athelia cancer and we have to take a step back and look at what are the first-line therapies and how do we define failure first so we'll spend a moment talking about that guidelines are relevant new new data and new guidelines are important in this subject area so this is a very good guideline to have as a reference if you don't know that aua guidelines are on an app you can download that and use that kind of in real time in your clinic but you can also take this information and just have it as a reference they have a nice table in the guidelines but this is my kind of recreation of the table and we know that the aua has tried to reclassify a non-muslim based of bladder cancer into some more kind of practical categories instead of the index patients that were in the old guidelines so in terms of low-risk there are very few patients that fall into this group but those are usually solitary low-grade TAS less than 3 centimeters or the entity of low malignant potential pun lump intermediate risk is recurrences of low-grade disease low-grade disease that's greater than 3 centimeters multifocal low-grade disease and then small high-grade TAS they also do put low-grade t1 in this group which is something I thought you should never see but I have seen more than once in the in the last few years and high risk is all the other people that have high risk the high-grade disease and we'll look at these a little bit more so in terms of what our guidelines for use of additional adjuvant therapy in low risk disease a single small low grade TA or con lump you should consider perioperative interval chemotherapy and I do think as dr. Lerner said that is the sort of perfect patient for a single of chemotherapy because you're not going to want to give them or going to need to subject them to six weeks of additional interval therapy later intermediate risk again the categories here these are patients where you should consider perioperative interval chemotherapy and should consider induction intra vesicle therapy and they don't really make a strong statement for or against mitomycin or BCG and if you do give BCG then one year maintenance is all that's necessary there's some data that shows that you can get away with only one year in intermediate risk disease that some European yo RTC data high-risk then they say should consider perioperative ensure vesicle chemotherapy there is some retrospective data that says even patients with high grade disease may confer benefit derive a benefit from that single dose but they really need the adjuvant therapy so this is where you should give induction interval chemo or intra vesicle BCG predominantly for this high grade disease and when using BCG the patient should try to get up to three years maintenance therapy so how how is in service code therapy used in the real world there's a recent publication that looked at about ten years of sere Medicare patient treatments this was in the 1990s to early 2000s but really in the real world there are still very low rates of BCG use this was all patients with what was high grade non-muscle invasive bladder cancer and after the first t you are in all patients who should be getting BCG there were only 40 percent shown to have BCG and after the first two you are so this is sixty percent did not get BCG over 20 percent got partial induction course about seven percent got one full induction course and only seven percent got induction plus additional maintenance if the patient if they looked at a cumulative use of BCG after multiple resections and so they saw that when a patient was having to go back multiple times so they had more ease sections if the patient had at least three resections then the overall use of BCG was up to 63% so we're getting closer to ideal and this was the breakdown so definitely more patients also getting induction plus maintenance by having more doses over there sort of records in seer in their Medicare administrative records there's very good data that shows that maintenance does improve response so if you gave BCG induction alone versus at least one course of BCG maintenance there's a 60 percent recurrence rate with BCG induction alone versus a 41 percent recurrence rate once you give an additional round of maintenance so you first have to ask was your first line management adequate using good surgical principles for making sure that you capture muscle in the specimen always trying to resect the disease completely potentially using enhanced imaging technologies if they're available to you with blue light or narrowband imaging and then judicious use of perioperative chemotherapy as I mentioned sort of selecting the right patient for that intrical chemotherapy installation certainly all high grade disease and most intermediate grade disease should undergo repeat resection within six weeks of the first resection we know that there's up to a 50% rate of persistent malignancy at that time of resection and even this 15 to 30% rate of upstaging so going from ta to finding T one or more importantly even having T 1 disease at the first resection and finding t2 upon resection and of course that rate is much higher if there wasn't the rate differential if you have muscle in the first resection is lower than if there's no muscle in the first resection you're more likely to find muscle invasive disease the second time and certainly it's been shown that the more d bulked the cancer is the better response the patient will have or the cancer will have - BCG therapy so then treatment failure in these entities that are non muscle invasive we have all these different missions of refractory resistance relapsing they get very confusing and hard to keep straight so they've gone away at least in terms of definitions and this consensus has come around for BCG unresponsive non-muslim vasive disease is started in 2015 with two different consensus groups describing these patients it first must be qualified that they've received adequate BCG they have two beliefs receive five of six doses induction and then unresponsive can be determined right away if they have high-grade t1 at their first evaluation after their induction course or you have to have given the patient at least one induction and either repeat induction or maintenance at least two of three doses and you find persistent or recurrent high grade disease within six months so this tries to harmonize a lot of these failures into one or two sort of easier to to categorize definitions and that's how that's enabled us to have better clinical trials as well for clinical trials using these same definitions as they enroll and evaluate patients it actually brings us closer to FDA approvals for drugs in this group so this is just a schema where you kind of go through the first couple of steps these patients with high grade disease receive a medication BCG if they have negative cystoscopy negative cytology they can continue on maintenance BCG if they have a positive Sisto and or positive cytology in the high-grade t a or T is you will continue on BCG as dr. Lerner said you could actually stay right on maintenance BCG some people would reach allenge with another induction course but if they have at that very first evaluation persistent or new high-grade T one that's already an unresponsive BCG BCG unresponsive disease you can then go on from repeat induction or maintenance and if you find additional high grade disease that's when you again call BCG unresponsive a couple of unique categories are when you have C is only disease as we've alluded it may take up to six months to see that carcinoma inside to resolve so you would not call a three month positive cytology or three month C is a failure and what if the patient has had a disease-free interval they might have even stopped BCG if you've had at least 12 months disease-free you could even consider reach Allen gene with BCG they may have responded they may have had good response initially and they may have now have a new and new occurrence of non-muslim vasive disease and when you take this patient to confirm the presence of persistent or recurrent disease there are a lot of key elements in the staging that are important you need to look into the upper tracks or at least do retrogrades or even selective selective washings if you do not see any visible disease in the bladder you definitely have to rule out a cult disease in the prostatic urethra you may also consider random biopsies or targeted biopsies based on your enhanced imaging to rule out carcinoma in situ in small areas in the bladder exam under anesthesia may also be important and and certainly making sure your CT urogram is current within six months and some of these high-risk features particularly lympho vascular invasion prostatic urethra involvement or multifocal or extensive disease these really pretend a much greater risk of progression so even if the patient has a TA or t1 right now these patients are more likely to come back with t2 t3 t4 disease and you're probably going to want to emphasize the importance of early cystectomy so we've established these patients or BCG unresponsive where do we go next radical cystectomy is our gold standard for these patients but as we've already had in our discussion there are a lot of patients who are either not willing or not fit to have that radical cystectomy so then we have Salvage interval therapy options only one is fda-approved but we'll talk about those that are available and then a fantastic array of clinical trials so interval therapy that has been described in research studies and in good usually phase 2 and some phase 3 data include BCG plus interferon value bacin or gemcitabine or gemcitabine docetaxel as a double it BCG plus interferon is something that had a good face to report and they showed that patients who had been BCG naive were 59% disease-free at 24 months if they had had prior BCG and now you added interferon the next induction they were 45% disease-free at 24 months but it really did not prove to be better than BCG alone the combination was thought to maybe reduce the toxicity or the side effects but that was hard to kind of recapitulate in the data and certainly they showed that there were poorer outcomes the more BCG the patient had already had that patient is relatively BCG resistance and interferon isn't gonna change that they did do us there was another large phase 3 study and there was ultimately no difference in effect plus or minus interferon sometimes in a BCG naive setting it may be worthwhile to include interferon but it will not necessarily salvage a patient who that's already not responding well to BCG Valery bacin is the only fda-approved option of all of these in traversable therapies but it is only fda-approved for a patient that has C is only in the bladder it's given weekly for 6 weeks um it did have a period where it was off the market so it sort of fell out of favor or knowledge or familiarity but in terms of results 18 percent of patients had a complete response at 3 months but at 12 months only 10% estimated to be disease-free and at 24 months only 2% in the trials that were published there was approximately 30% of patients went on to cystectomy by 2 years so it may have a role but it doesn't seem to have a very durable effect and I don't know that it's used widely at all single agent gemcitabine has also been described in single single agent non randomized trials and this is 2 grams in a hundred millimeter 100 millilitres of normal saline the sort of planned schedule is six weekly doses and then monthly for 12 months in these patients there was a nice effect that was durable 28% of patients were disease-free at 12 months 21 percent of patients disease-free at 24 months and keep in mind these are patients who you've already decided didn't respond to BCG and I'm sorry their disease didn't respond I'm trying to change my terminology so out of 47 patients total we are happy to see that the majority of them had high grade disease so we can trust this as effective but only two of the patients in the trial had high grade t1 so a word of caution certainly if you're trying to give a if you're trying to salvage a high grade t1 with gemcitabine if you add docetaxel to gemcitabine it's a little bit of work for the patient they have to stay in your clinic for maybe three hours to get this treatment but ghin side of being in 50 emails of sterile water 90 minutes in still time and docetaxel in normal saline for 120 minutes there was no set maintenance course recommended but they had 66% complete response at that first 3-month evaluation and 34% disease free without recurrence out to two years johns hopkins had a their own prospective trial or prospective cohort and they had 42% of these patients without high grade recurrence at two years and interestingly or another way to look at that is that they avoided cystectomy in 64% of their patients who had high-risk disease so it really does have a potential value in particularly those patients that you are very worried about performing such a huge operation on it certainly is better for BCG naive than BCG faylene disease generally speaking when someone's cancer has been resistant to BCG it's more likely to be resistant to anything else you might try so just always keep that in mind clinical trials are really the future here there are many trials right now looking at checkpoint inhibitors Pember lism ab is in a multicenter international multi-site phase 2 study using by merck there also is a swag 1605 studying at s ilysm AB for BCG unresponsive disease develop this is a single Center it looks like and also even combining a checkpoint inhibitor with additional BCG there are several different trials looking at interesting vaccine therapies to try to bolster the immune system so the patient continues BCG but you give them something else that's thought to enhance their own innate immunity like one of these particular proteins there's also ensure vesicle Visenya that trial has closed accrual and has not yet reported outcomes there's also adenovirus angka lytic kind of absorbed agents and even a different preparation of interferon that can be given in addition to BCG it's just something that's pretty exciting if you go on clinical and ask for trials on bladder cancer there are almost 250 interventional trials going on right now this is in all different disease states I'm not talking only about non-muslim base of disease but I think it makes all of us who treat bladder cancer really excited to see that much energy and ongoing investigation some some details for other ideas that you can try to improve your results with BCG there are two trials for BCG naive patients one is also through the co-operative groups swagg 1602 is looking at intradermal BCG before giving intra vesicle BCG it's thought to jumpstart the immune response to make the cancer more responsive to the intra vesicle installations it also is bringing the Tokyo strain which is not currently approved in the US trying to bring that into a clinical trial to try to get that approved because as you all may know we had a huge BCG shortage and the Connaught strain is no longer being produced so if we were to have another shortage of BCG it would be nice to have more options in terms of where to source that from and they may have different ethic efficacies because of how they've been derived over the years and there are a lot of valuable translational correlates going on with this with this trial there's also this interesting interleukin super agonist that is also driving the immune system stimulating natural killer cells stimulating t-cells and giving this in the bladder in conjunction with BCG trying to really augment the BCG response so there are some things being studied right now and you know of course BCG is our mainstay we do not want to abandon the very first immunotherapy that's been available for for cancer in general and certainly in bladder cancer for good references the NCCN guidelines here's the link to go to that certainly the AU a non muscle invasive bladder cancer guidelines as well these are the two BCG unresponsive statements that try to harmonize and summarize those patients and then looking for clinical trials or looking for ideas clinical has become a little more user friendly to search and understand and then even the bladder cancer advocacy network has a clinical trial dashboard available online for other resources you