Highlighting Clinical Trials NonMuscle Invasive Bladder Cancer Part I

okay just to start with some basics on the anatomy I have here two pictures highlighting the bladder and the associated or adjacent structures so the bladder has two functions it is a storage organ and it is also a muscular structure that can force the urine out so they but the urine is made in the kidneys as the blood is filtered and the urine travels down the ureters the ureters then lead into the bladder and the urine is stored in the bladder a normal adult bladder holds about 350 400 milliliters of urine and the bladder has nerves that control the sensation in the contraction or the muscular function so when the bladder is full it will send nerve signals that tell an organized neuronal structure that it's full and then there will be feedback to allow it to expel that your the urine then is expelled through the urethra and you can see the urethra in the mill traverses the prostate and the penis and in the female it shorter traverses underneath the pubic bone their bladder cancer develops because in the vast majority of cases because of a genetic predisposition with an environmental insult and the genetic predisposition is usually not hereditary it's it's just that the bladder as it developed had some genetic changes that are normal with development and then there is an environmental insult in most cases it's tobacco but it can be other types of carcinogens in the environment and so the urine sits there in the bladder and over time the environmental toxin and damage the cells of the bladder and bladder cancer can form bladder cancer is more common in men than women but a substantial number of women are affected by bladder cancer these are some celebrities that have been afflicted with bladder cancer bladder cancer is the ability to stay without having to remove the bladder because of the access through the urethra urologists have been able to treat bladder cancer for a long time using the receptor scope as shown up in the top right corner this is how bladder cancer is diagnosed and it's typically diagnosed because patients have blood in their urine so called hematuria so the urologist would place a scope into the urethra often in the office just to visualize the tumor and then subsequently resect this in an operating room the goals of resection are to remove all of the tumor but also to go deep enough into the muscle of the bladder in order to properly stage the tumor and so when I say properly stage the tumor what I'm referring to is the AJCC staging for bladder cancer which is shown here if you look on the right-hand side there's a kind of display of different types of tumors the first one is CIS or carcinoma in situ this type of tumor is confined to the uracil ium for the superficial compartment of the bladder we termed these as non invasive so the CIS and the T a tumor are non invasive because they don't penetrate that green membrane layer also called the basement membrane there above that superficial - that so they're non invasive T one is invasive it does invade through this basement membrane but it's not muscle invasive so it does not go to the red layer or the muscle layer a t2 is defined by invasion invasion into the muscle and t3 would be invasion to the fat surrounding the muscle now it's an important distinction between t1 and t2 because in the US and and in in the world the muscle invasion is typically managed with removal of the bladder or with other modalities such as radiate radiotherapy whereas those tumors that do not invade the muscle we often try to preserve the bladder first the goal today talk about clinical trials and non-muslim vasive a bladder cancer and I just want to talk about the goals for non-muslim based disease and how those are different for compared to muscle invasive disease let's look at the right side of the panel and start with the muscle invasive or high-risk disease first in this case the tumor has gone into the muscle layer as we saw on the last slide and it now has access and ability to spread to other parts of the body including organs such as the lung or the liver which is or to commonplaces a platter likes to go and so in this setting what we want to do for the patient is to prevent the spread prevent spreading to the lungs for rent spreading the liver we want to prevent death from prostate cancer because when bladder cancer has spread to other organs it is very difficult to treat the survival in those patients is drastically diminished because of metastatic disease and so our goals in the very advanced stage is to prevent metastases and then to minimize the complications that may be associated with treatment and preserve patient's quality of life this is different for patients with non-muslim visa disease because the risk of metastasis is very minimal if not rare and as long as non-muslim invasive disease is managed well we don't have to worry too much about metastasis so our real goals are different and they and the goals here are preventing disease recurrence and what I mean by recurrence is tumors coming back to the bladder unfortunately bladder cancer has a very high recurrence rate so even after the tumor is successfully removed surgically the recurrence rate can be as high as 40 or 50 percent and in some cases up to 60% without treatment so our goal is to prevent the tumor from coming back into the bladder and we want to prevent progression and what I mean by progression is moving of a stage from let's say a low stage tumor to a higher stage so as an example patient has a T a tumor superficial non invasive tumor rushon would be a change from TA to say t1 or t2 and that's progression and we want to prevent progression we also want to minimize side effects from treatment and when I mean my treatment here is usually installation of a medication into the bladder these patients because of their high recurrence rate we are often looking to the bladder multiple times to survey the bladder these patients end up undergoing a lot of procedures throughout their lifetime so one of our goals is really to try to minimize the number of procedures to improve the effectiveness of our treatment so that we don't have to do as many procedures so how can we combat bladder cancer what are our strategies what are the ways that we can improve the care for our patients this for different means kind of summarize the different ways that we can do this one is to prevent the tumor from ever coming and so there's prevention strategies once the cancer has been detected we could work on strategies to I just detected earlier so this would be with screening an example of screening is mammography for breast cancer or colonoscopy for colon cancer we have discussed and people have done trials in screening for bladder cancer for example using a urine dipstick test to monitor for blood in the urine there was a very classic study where this is done on quite a few persons of at the age for developing bladder cancer and there was some evidence that weekly screening with a dipstick could actually identify tumors in an earlier stage number 3 would be improving the efficacy of current treatment that would be a typical of a clinical trial using a new medication a novel medication or maybe a combination of therapies or there's different types of approaches but that would be geared toward improving the efficacy of a current modality and finally increasing the adverse effects of treatment and improving quality of life is another way that we can combat this disease why are clinical trials needed why are they important and how has this impacted practice I want to give a classic example of a very recent study that I think hits home for me so this is the vitamin E and selenium story so vitamin E and selenium were for a long time considered to be potentially protective in terms of preventing prostate cancer most people feel that vitamins are pretty safe there was some actually some good animal evidence and pretty from what we call preclinical data that vitamin E and selenium and high doses could actually prevent prostate cancer from developing and there was even observational studies among persons that had been taking these vitamins to suggest that they could prevent prostate cancer but these observations and these studies were really not randomized controlled clinical trials and so until we had a adequate randomized controlled clinical trial the world pretty much believed that vitamin E and selenium could prevent prostate cancer so what happens when the clinical trials are actually done so there was a large recently a large clinical trial randomized control trial where people were given vitamin E and selenium compared to a placebo or control and it turns out we were wrong selenium did not prevent prostate cancer and actually there was a suggestion that vitamin E and high doses could actually increase the risk of prostate cancer there was a a non significant increase in the risk of prostate cancer and I say non significant because the p-value was 0.09 the significance of an association what we consider significant is a p-value of less than 0.05 so while it wasn't significant it was pretty darn close and this has caused a lot of us to kind of you know rethink the influence of vitamin E and selenium now this I want to point out this is high doses of vitamin E not the doses you get in a multiplexer a standard vitamin but the bottom line is that without this clinical trial without the participation of these patients and the investigators and all the people that put the work into doing this we would never know the the real influence of these these agents and unfortunately in this case it was a negative result but this shows the importance of why clinical trials are needed what are the benefits to participating in clinical trials these from a patient's perspective one is that there are through clinical trial enroll involvement there's access to new treatments that are not yet available a good example this is the new immune therapies that are out for bladder cancer there's a lot of excitement for these drugs one of them was recently approved by the FDA the reason for the excitement is because these drugs are showing activity that we've never seen before we've been treating advanced bladder cancer with high-dose chemotherapy since the 1960s and 70s and now there is a new agent that these immune therapies that are showing effectiveness in in patients that have failed chemotherapy so a lot of people are rushing to get on the trials and it's you cannot get the drugs without participation through a clinical trial because they're not currently fda-approved the other benefits would be that you're obtaining expert medical care the trials have been run through multiple investigators multiple groups so that there's a consensus on the therapy that is provided and on the process in terms of the imaging and lab tests and things like that that are done both before and after treatment so you're really getting outstanding medical care and there's multiple people involved in your care coordinators that are making sure that things are getting done physicians investigators so it's a a more hands-on and more attention to your medical care you play an active role in your own health care do you make decisions about whether or not you want to participate so it gives patients that responsibility and keeps them as active players in their care and importantly it provides help to others that would be coming after you and in terms of contributes the value of research what are the risk involved with clinical trials well I think most importantly is we don't know results the vitamin E and selenium is a perfect example we didn't know that that high dose vitamin e could have a slight increase in risk we thought it would be the complete opposite so with any clinical trial we are taking a risk because we don't even in the best case scenarios we really don't know if the drug will be beneficial and that's what the reason for the trial and there may be even if it is beneficial there may be untoward side effects that make it not worth taking and some clinical trials and some drugs are particularly toxic and for example a phase one trial may be an alternative phase one trial we do a dose escalation where the goal is to increase doses over a period of time and in some cases the increased dose could be could render some unpleasant side effects that may may cause the patient to come off of the study or the investigator to ask the patient to come off it can also have some kind of unaccounted for expenses traveling time you want to ask things like how many extra visits are involved with this study is there any compensation and health insurances may not cover the cost of all particular things in the study and it's something to to discuss with the position rope briefly I want to talk about the different stages of non-muslim base bladder cancer and I've classified them as low risk for example the patient the patient with a low grade D a tumor this is a superficial tumor low grade it's really has a very very low risk for progressing to t1 or touched it to a other tumor then there are patients with high grade T a high grade t1 their nan muscle invasive CIS is an example of this in these patients that are BCG naive meaning they've not received BCG before and then there are patients that have received BCG but the tumor has come back and that's the BCG unresponsive patients so currently how do we manage bladder cancer we were talking about intro vesicle treatment before this is an example of what we mean by this so a medication such as BCG or mitomycin c is instilled into the bladder it's often allowed to dwell in the bladder for a period of let's say one or two hours and then it's removed it's really remarkable that that in terms of its ability to treat bladder cancer or BCG is probably one of the most effective cancer treatments available and it's the second fda-approved immunotherapy for cancer that was ever approved so in many ways we're very fortunate to have access to the bladder mucosa and in our ability to treat a lot of cancer through that mechanism with these different stages if you will of bladder cancer there's different types of treatment for example in a low-grade d 8 patient we typically would not give BCG and the clinical trial in that scenario might be aimed at trying to minimize a number of procedures I'm aware of this trial that is looking at minimizing the number of surveillance system piece in the u.s. we there's a different strategy for doing surveillance then it's using the European system and so when clinical trial would be to compare the US versus the European system in terms of surveillance strategy for the BCG naive high-grade non-muscle invasive disease an example would be combining BCG with another therapy or somehow improving the efficacy of BCG and finally in the BCG unresponsive disease State there are several clinical trials currently available or going to be available I'm using two protective immune therapy these patients are often counseled to undergo bladder removal so having new therapies available for these patients is greatly sought after because we want to be able to offer something besides splatter removal you