Neoadjuvant & Adjuvant Chemotherapy for Bladder Cancer - Bitly

Neoadjuvant & Adjuvant Chemotherapy for Bladder Cancer Part I: Bladder Cancer Basics & An Introduction to Chemotherapy May 23, 2018 Presented by: Dr. Matthew Galsky is a medical oncologist focused on the care of patients with bladder cancer. He received his medical degree from Tufts University School of Medicine and subsequently completed training in Internal Medicine at Beth Israel Deaconess Medical Center, Harvard Medical School. He completed a medical oncology fellowship at Memorial Sloan Kettering Cancer Center where he subsequently joined the faculty. In 2010, he was recruited to the Tisch Cancer Institute Ichan School of Medicine at Mount Sinai as Director of Genitourinary Medical Oncology where he is currently a professor of medicine. Dr. Galsky's research has focused on the clinical development of novel therapies for bladder cancer and team science based approaches focused on dissecting the mechanistic under findings of response and resistance to novel bladder cancer therapies with a particular focus on immuno-therapeutic approaches.

Dr. Galsky: I'm going to make a couple comments before I start. One of which is that I'm going to start out very basic and that's certainly not to minimize anyone's pre-existing knowledge of this subject area but I just want to make sure that everyone is on the same page. The other comment is that I'm going to try to stay away from very specific data in terms of going deep into the woods and really focus more on general concepts but I will be showing some data as well. Because I think it is necessary to reinforce some of the concepts and make sure that everyone understands what a clinician is thinking about when they're making some of these treatment recommendations. So, to set the stage of course, the bladder is an organ that sits towards the bottom of the pelvis and it's connected by these long tubes called the ureters to the kidneys. The kidneys filter the blood, maintain balance of fluid and electrolytes in the body, filter toxins and that creates the urine, of course, which drains down the ureters and gets stored in the bladder. The bladder is just that, it's a storage device for urine. You can see the wall of the bladder here. The bladder is a relatively thick-walled organ. You can see that this is blown up in this cartoon here. What I want to point out here, is that, like every organ in the body, the bladder is made up microscopic cells and you can see these cells here with the nucleus in purple. Cells are the building blocks of all of our organs and normal cells in our body have a fixed life span, they do their job and then they die and new cells come to take their place.

Neoadjuvant & Adjuvant Chemotherapy for Bladder Cancer Dr. Matthew Galsky

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For reasons that we don't understand, sometimes an abnormal signal occurs in an individual cell. This really occurred just in one cell, a mutation in the DNA, related to some exposure, related to the environment, related to inherited genes perhaps. In that mutation helps the cell that instead of dying that natural process, it should continue to live. That cell can divide, like all our cells can divide but it's offspring inherits that abnormal signal. So, that cell continues to grow and divide as well. So, if you all these cells that are growing and dividing without dying, then they start to accumulate, and they form masses or tumors. That's what cancer is, starts out as one cell in the body that gets its abnormal signal that tells the cell to start to grow uncontrollably and accumulate. So, you can see normal cells lining the bladder here and there's also in this cartoon, some representations of bladder tumors. Collections of cells that started to grow in this abnormal pattern. When cancer of the bladder occurs, it typically starts on the inside wall of the bladder and that's why when the urologist, when they put their scope up into the bladder they can see the tumor. Because, they are looking at the inside wall. That's also why, not uncommonly, a presenting sign of bladder cancer, is blood in the urine because this tumor irritates the lining of the bladder and then red blood cells pass in the urine. When bladder cancer grows, despite it starting on the inside wall of the bladder, typically, the growth is deeper into the wall of the bladder. In this area, right here, labeled muscle, is a very important landmark in the management of bladder cancer. When that layer in involved with cancer, we call that muscle invasive bladder cancer. It's an important landmark because we know that the risk of bladder cancer growing and progressing and spreading is higher once that layer is involved. Therefore, typically, once that layer is involved, a standard part of treatment is removal of the bladder, or cystectomy. There are some other forms of definitive treatment like radiation as well, but surgery is one of the back bones of treatment for muscle invasive bladder cancer. Surgery for bladder cancer for muscle invasive bladder cancer can be a curative approach. It's a curative approach in many patients but we know that the deeper the cancer invades into the wall of the bladder, the less likelihood that it will be a curative approach. We know that because, if we monitor patients’ years, months to years after treatment for bladder cancer, after having their bladders removed, a subset of patients will develop recurrence of the cancer. The cancer will show up somewhere else in the body and that's reflected on this figure here which is called the KaplanMeier curve. Just to orient you here, in the x-axis is the years after surgery, so the years after cystectomy. In the y-axis, shows the probability that the cancer hasn't come back. So, everyone at time zero starts out at 100% because no one's cancer has come back at time zero. But as time passes, you can see that there is an increasing likelihood of the cancer


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coming back, up to about four to five years and then this levels off. We know that the risk of the cancer coming back or recurring after that time is much lower and that's why we usually talk about a five-year survival as this important landmark time point as the likelihood of cure after that time is substantial. Shown here, in addition to the likelihood of cancer recurring after surgery is the finding that the deeper the cancer invades into the bladder, the higher the likelihood that the cancer might come back and that's going to be important a little bit later when we talk about adjuvant chemotherapy. So, when a cancer of the bladder is diagnosed, the first thing, of course that's done, is that the cancer is staged. Staging is just our term for understanding where the cancer is and where it isn't. One of the most important components of staging is the depth of invasion into the wall of the bladder and determining if the cancer has invaded into the muscle layer or not. But, another component to staging is determining if there is cancer elsewhere in the body. We typically do that with things like CAT scans or MRI's. So, you might be wondering, and it's really a very appropriate question, if I have a CAT scan or a MRI before surgery and there's no evidence of cancer and then the cancer is removed surgically; the bladder is removed surgically, how can the cancer come back, how can there be a recurrence? This term recurrence is really a misnomer, because it's not that cancer magically recurs, but even before surgery, unfortunately in some case, there will be microscopic spread of the cancer and our current technology, in terms of CAT scans and MRI, as much as that's improved over the years, is still quite limited in our ability to detect small amounts of cancer. But what I've shown here is various degrees of volumes of cancer cells and what that would equate to, to a size on a CAT scan. You can see here, that one centimeter, which is about the limit of detection on CAT scans or MRI's. We're getting a little better at seeing things less than a centimeter but often very difficult to know what something might represent when it's less than a centimeter in size. A one-centimeter mass on a scan represents a collection of about a billion cancer cells. So, when a CAT scan doesn't show evidence of spread or an MRI doesn't show evidence of spread; ultimately what we're saying is that there's probably not collections of cancer cells that range in the billions but we can't definitively rule out smaller amounts of cancer that might have spread. We have a very difficult time differentiating no spread of cancer at all from spread of 1000 cells or spread of a million cells. This is the really the crux of the issue here in terms of understanding whether or not surgery alone will be curative or not and if we could detect these small amounts of cancer cells in a reliable and reproducible way then that would certainly enhance our ability to individualize treatment. There are attempts to study novel methods to improve upon our abilities here, but right now we really rely on conventional CAT scans and MRI's to make this decision.


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So, if there are a subset of patients who have microscopic spread of cancer, then we know that removing the bladder alone will likely not address those collections of cancer cells because they have already spread outside of the bladder. So, about three decades ago, a concept was developed on, not just in bladder cancer, but in various types of cancers that was based on the hypothesis that if we could use surgery to adequately control or remove the primary tumor, then perhaps we could use systemic treatments, like treatments administered intravenously that would flow wherever blood might flow in the body, chemotherapy, to kill microscopic cancer cells which might have spread. That's an important point; that might have spread, because that's relevant in terms of how some of these treatments have been developed and how we interpret some of the data. When we give that treatment, when we give systemic treatment, like chemotherapy, prior to removal of the bladder, it's called neoadjuvant chemotherapy. When it give it after, it called adjuvant chemotherapy. There are some pragmatic and some scientific reasons why giving chemotherapy first prior to surgery vs. after surgery might be more beneficial. From a practical standpoint, because surgery to remove the bladder is not insignificant surgery, often times it's easier for patients to tolerate chemotherapy when it's given prior to surgery compared to after cystectomy. Another consideration with giving chemotherapy prior to surgery is that, while I said that we're talking about cancer that might or might not have spread, and so in an individual patient, it's difficult to impossible to know if the chemotherapy has provided a benefit. I'll expand on that point a little bit more later. When chemotherapy is given before surgery, we can determine the response to treatment within the bladder itself when it's removed and that can often serve as a prognostic indication as to how microscopic cancer might have responded to chemotherapy, if indeed it was present. When we give chemotherapy after surgery, as I mentioned, it's called adjuvant chemotherapy and a major consideration with giving chemotherapy after surgery is the fact that after the bladder is removed and is analyzed by the pathologist in the laboratory, we really get a much better, a much more precise indication of how extensive the cancer is locally in the bladder and whether or not the lymph nodes are microscopically involved. So, our ability to prognosticate, our ability to guess whether or not cancer has spread microscopically is enhanced by that information.

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