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Treatment of Recurrent Disease Q & A
Deborah Armstrong, M.D.
Medical Oncologist

General Q&A about Recurrent Ovarian Cancer

Q&A about Angiogenesis Inhibitors

General Q&A about Recurrent Ovarian Cancer

What is recurrent ovarian cancer?
70-80% of patients are initially diagnosed with advanced disease, i.e. disease that has spread outside of the ovaries. Obviously, one of the many things that scientists are working on today is trying to find ways to diagnose patients when their disease is still localized to the ovaries, so that their disease can be cured by surgical removal of the ovaries or diagnosed before the cancer develops. For the vast majority of ovarian cancer patients, the initial approach to treatment is surgery. This is unique for ovarian cancer; for most other cancers that have spread beyond the site of origin, we don't do extensive surgery. However, for ovarian cancer we know from a large number of studies throughout the last two decades that patients who have an aggressive, up-front surgery do better. We're going to be talking about that, because that's one of the controversial issues in recurrent disease, whether there's a benefit to surgery. After surgery, standard care in the US involves administration of a combination of a platinum drug and a taxane, usually Taxol® ([MEDLINEplus information about paclitaxel]). Recently, data suggests that Taxoted® ( [MEDLINEplus information about docetaxel]) is an effective agent in combination with platinum as well. The good news for patients with ovarian cancer is that patients who undergo a combination of surgery and chemotherapy will go into a remission. This has prompted many of us to look for ways that we can add new treatments to initial therapy in order to maintain and prolong those remissions or to actually prevent disease from returning. That's one of the things we'll be talking about in terms of clinical trials in recurrent disease and how the information from these clinical trials can help us in regard to initial therapy. Unfortunately, most patients who go into remission with their initial therapy will relapse as well. The numbers suggest that between 70-90% of patients with ovarian cancer will, at some point in time, have a recurrence of their disease.

How are patients monitored for recurrence?
Follow-up care includes bimanual pelvic examinations, serial measurements of either CA125 or other tumor markers, one or more imaging studies reassessments and, more controversially, second-look laparotomy. Imaging studies generally include a CT, but not excluding a PET or even a CT/PET combination. However, recurrent cancer has a large spectrum of behavior making it relatively difficult to diagnose a relapse and determine the aggressiveness of the tumor.

When is treatment re-started?
There is a fair bit of controversy about when to restart treatment. Small tumors generally respond better to treatment, therefore early detection of recurrence may be useful. Although the use of frequent clinical follow-up visits can detect recurrence earlier, it is important to note that the benefits of early introduction of salvage chemotherapy are limited and may intrude upon the patient's symptoms and treatment-free survival.

How do we define a relapse?
Is an elevated CA125 alone enough to define a relapse? Most patients are very much keyed into their CA125, and even small changes in the number prompt a lot of anxiety and concern. It's important to note that in a patient who does not have any symptoms of disease recurrence, doesn't have any physical exam evidence, doesn't have any evidence from radiographic imaging such as CAT scan, it's not entirely clear that rising CA125 alone should prompt re-treatment. For example, there certainly are causes other than relapse that can induce a rise in CA125, particularly a transient rise in CA125, i.e. a bump that comes back down. Because many other things besides ovarian cancer can cause CA125 to rise, this test is not a very good screening tool for initial diagnosis of ovarian cancer.

What happens when your CA125 rises consistently, month after month? Is there a particular level when most oncologists treat based on the CA125 alone?
The answer to that is variable. I feel pretty strongly that an asymptomatic patient with no evidence of disease would not be helped by treatment based solely on CA125 elevation. Most people will say that once a patient has symptomatic disease, radiographic evidence of disease, or physical exam findings of disease, treatment should occur immediately. What we're trying to do is balance deferring treatment for recurring disease for as long as possible with not having to treat large volumes of disease. The question is, particularly with the CA125 elevations, how long can the CA125 rise before you have evidence of disease on CAT scans, physical exams, or patient symptoms? The answer varies from patient to patient. Some patients don't have a sensitive CA125 and will develop evidence of disease before their CA125 is outside the normal range. I've had patients who have had a continuous rise in their CA125 for over two years before they had any evidence of disease. Although there is certainly a period of some anxiety, I don't think that we benefit patients by treating them in that interval. There is a lot of controversy about that, and not all physicians agree with this delay.

How is recurrent ovarian cancer treated?
Once we've decided to start treatment for recurrent disease, what are some of the things we have to take into account? What are some of the factors we have to think about when deciding about treatment? Because there are many treatment options, these are all, I think, critical issues. The first one, and perhaps the most important in predicting how a patient is going to respond to therapy, is what we call the treatment-free interval. How long has it been since the patient ended her initial therapy until her return? The kinds of treatment options you have and the kinds of responses that you can expect for someone whose interval was three months is very different from someone whose interval is three years. The other questions we have to ask is how many prior regimens has the patient had and what kind of toxicity did she have? In particular, did she have a lot of trouble with her** bone marrow toxicity, lowering of the blood count. Did she require growth factors like Filgrastim/Nupogen/G-CSF ([MEDLINEplus information about CSFs]) or Procrit®/Epogen®/epoetin a ([MEDLINEplus information about epoetin])? Did she need transfusions of red blood cells or platelets? What kind of symptoms did the patient have when her disease returned? How was the patient's performance status, which tells us how close the patient is to her normal level of functioning, during first-line therapy? What kind of disease volume are we dealing with? In particular, it's important for some patients who might have GI symptoms related to their disease recurrence, if they have disease in the abdomen that may limit some of our treatment options.

What are appropriate goals in treating recurrent disease?
We know that many patients whom we treat in the recurrent disease setting will go into remission, but not all patients will. One of the things we have to ask ourselves as we start out on therapy is, are there any treatment choices that I might make today that might impact my treatment options down the line? That's particularly important for patients who have an early time of disease recurrence. For example, the patients whose disease recurs 6-9 months after their initial therapy, while very treatable, the chance of those patients going into another complete remission is actually small. We have to recognize that whatever treatment we start out with, six months down the line, if the patient has had a minor response or a partial response to therapy or if she has had an even, stable disease, sometimes the treatment choices that we make are limited later. In other words, you can't continue that therapy for six, twelve months, an even longer period of time, even if the patients are benefiting, because accumulative toxicities must be taken into account. That's one of the main factors that I look at in the treatment choices that we have. Are there toxicities from therapies that you'll get six months down the line that you don't have two or three months down the line? So our goals, obviously, are to prolong survival for patients and to delay progression. We'd certainly like to control disease-related symptoms, but we'd also like to minimize treatment-related symptoms. I think that's particularly important for accumulative toxicities, those toxicities that tend to get worse with time, and obviously, we'd like to maintain or improve the quality of life. I think one of the things, for both patients and physicians, is that in the setting of recurrent disease, we go through a shift in our approach. I think up front, all the patients and physicians alike are hoping that this is a situation where we'll cure patients, that we won't have a relapse, but once we have documented a relapse for our patients; I think we have to shift those gears a little bit. What I think is most helpful is to actually think about treating ovarian cancer as a chronic disease, just like we treat diabetes or high blood pressure. You have to think about this as a disease that, while it might go into a remission, will never go away completely. You have to think about treatment down the line. Some things we consider really cardinal points in the management of chronic diseases. This is true for any chronic disease: high blood pressure, diabetes, etc. As physicians, we need to understand the natural history of the disease and recognize how the disease progresses, and realize that the manifestation of the disease is going to be different from patient to patient. We need to anticipate impending decision points. If I see a patient, I think to myself, if I had to treat that patient today, what would my choices be? And if I had to treat that patient six months from now, what would my choices be? Those choices are sometimes quite different. I think we have to also perceive that over-treatment can be as inappropriate and dangerous as under-treatment. I have seen a number of patients with few symptoms from their disease but they are really suffering from the treatment. I think those are the patients who have been inappropriately over-treated. Another thing that I think is extremely important is that patients need to be educated about treatment options and they need to be able to participate in the decision-making process. For any chronic disease, this is essential. For ovarian cancer, patients need to be able to get information that they need, they need to be able to set goals for their therapy, they need to have realistic expectations from their therapy, and they need to be able to participate in decisions. I think these are all important to be able to balance out the hope and positive thinking that are necessary to go through treatment and to be able to cope with disease. I think that's where, as physicians, it's our job to educate patients in regard to treatment options that may be available in general and which may be best for an individual patient. We do have to recognize that what may be good for one patient may not be appropriate for another patient and that's where I think you all, as patients, need to have good working relationships with your physicians.

What are the options for treatment of recurrent ovarian cancer?
By and large, we're talking about chemotherapy. When we talk about chemotherapy, we actually have a pretty long list of options at this point in time. The first thing that we usually address is, is it reasonable for us to think about reusing the agents that we've used as part of initial therapy? That's by and large platinum drugs and the taxanes, either Taxol® ([MEDLINEplus information about paclitaxel]) or Taxotere® ([MEDLINEplus information about docetaxel]). One of the most important findings that we have made over the past decade or so is, again, that issue of the treatment-free interval. The longer it's been since your initial therapy, the higher your chance of responding to retreatment with taxane drugs like Taxol or Taxotere and the platinum drugs. This is actually true for all the other agents that we have available. We do know that if it's a very short time — 3 to 6 months from the completion of your initial therapy — patients don't have a high chance of responding to retreatment with platinum drugs and the taxanes. However, if you can defer those therapies until down the line, the chance of responding is actually going to go up. We believe the reason for this is whatever disease was left over at the end of initial treatment, that's the disease that by definition has survived the platinum and the taxane drugs and has developed resistance. We also know that that resistance is lost with time so, for example, if your cancer cells are not exposed to a platinum drug or a taxane for a year or a year and a half, your chances of responding to retreatment are going to be higher. That's true even if another chemotherapy is given in the interim. I think one of the important issues with this is that sometimes the knee-jerk is to say I had a very nice response to Taxol/platinum up front. Let's use that again. What you're treating now is disease that's different because it's disease that has survived through Taxol platinum. Many of us, particularly patients who relapse early (and by early I mean usually within a year or so of their initial therapy) ought to think very hard about using alternate agents, because later on we may go back to using the platinum drugs or the taxanes. There are four drugs right now that are out there that have been shown to be effective in patients that have received a taxane drug and a platinum drug. These drugs are topotecan ([MEDLINEplus information about topotecan]), Doxil® ([MEDLINEplus information about doxorubicin]), oral etoposide ([MEDLINEplus information about etoposide]), and gemcitabine ([MEDLINEplus information about gemcitabine]). There's another group of drugs that's been out there for a longer period of time and the data supporting the use of those in recurrent ovarian cancer dates back to before the era when we were routinely using taxane. I think the criteria for those agents are not quite as stringent, and this includes drugs such as tamoxifen ([MEDLINEplus information about tamoxifen] ), which is a hormonal agent, ifosfamide ([MEDLINEplus information about ifosfamide]), a drug called altretamine ([MEDLINEplus information about altretamine]), and another drug called Navelbine® ([MEDLINEplus information about vinorelbine]). Those are all agents that may have some utility in ovarian cancer, but we don't really know how they stack up with these other four agents that have been tested rigorously in the setting of taxane and platinum refractory ovarian cancer. With regard to these agents, what I tell patients when we're thinking about treatment is that under ideal circumstances, we're going to use all of these agents at one time or another. The question isn't which of these agents did we use, but what order did we use them in. When you sit down and review the toxicities of these agents, you recognize that some of these agents, in particular the ones that lower blood counts, cause a greater drop in blood counts with the passage of time, if patients have prior chemotherapy. So, for example, a drug like Topotecan®, we know very clearly that the more prior therapy you've had, the lower your blood counts are going to be when you get that treatment. So we tend not to like to use that as the fourth or fifth treatment. It's probably better used as the second or the third treatment. Other agents like Doxil, for example, don't lower the blood count as much, so that's a drug that may be best used and will still be safe in regard to blood count if you use that further on down the line. The other issue with regard to these agents is cumulative toxicity. Again, for many patients who don't go into a complete remission and who don't have all of their disease eliminated, sometimes six months down the line when someone's had a partial response, for example: someone had fluid on her abdomen. Now the fluid's gone, but the measurable disease hasn't really shrunk all that much. That's technically someone who has stable disease. Six months down the line, you know that patient has benefited, but sometimes you get into a problem where the therapy is starting to cause more and more toxicities with each cycle. Then you have the option of either increasing the time between the treatments or cutting the dose, and those are things that can potentially cut into the effectiveness of the agent. I think it's important to try and avoid agents that have significant toxicitiy. One of the big problems with carboplatin ([MEDLINEplus information about carboplatin]) is that it causes the loss of platelets in patients who use this agent. So, particularly if we're treating a patient who was treated with carboplatin, we're going to have a lot of trouble with platelets. Then we're going to have to compromise on the dose and the schedule. So, when I talk to patients about our criteria for continuing this therapy, I emphasize that their disease is not getting worse and they're tolerating the therapy, so potential treatments are all about effectiveness and toxicity. What we mean by saying the disease is not getting worse, is that a stable disease is a benefit for patients whose disease grows rapidly. In other words, you can stop the cancer cells from growing, but you may not be able to get them to go away altogether. We recognize that and many treatments that we have today have a much higher stable disease rate than they do a response rate. I think this is important considering this a chronic disease. We'd like to be able to put everybody into another remission, but we recognize that we can't always do that. So, if we're using an agent, we'd like to minimize the toxicity of it, and that may be best juggled by the order in which we use these agents. You'd also like to maximize the number of agents you can use and I think, particularly with regards to using the platinum drugs and the taxane, if you use another agent in between time that it will increase the chance that you will respond to the drugs as well as decrease the chance that you will have accumulative toxicities from the treatment.

What is the role in secondary debulking surgery in treatment of recurrent disease?
We talked a little bit about how important surgery is with initial diagnosis and therapy. The question that always comes up is would patients who have recurrent disease benefit from that kind of therapy as well? The honest answer is we don't know. Because of the way ovarian cancer tends to spread, with little cells shedding off the surface of the ovary and moving throughout the abdominal cavity, we know in the recurrent disease setting, there's not one large lump or mass that can be easily removed by the surgeon. Lots of times, there are multiple, little sites of disease that are not really amenable to surgery. It's probably not in the patient's best interest to undergo a surgical procedure unless there's very clear-cut evidence that the disease can be removed surgically. The other thing that we know is that when patients undergo surgery for ovarian cancer, it's very rare that we're able to remove all the disease. What that means is that since there will be disease left behind, the disease will not have a high likelihood of being very sensitive to chemotherapy. As a result, the patients probably won't benefit from surgery because the disease can grow back quite quickly. For that reason, we tend to use surgery in the recurrent disease setting for patients who have been out more than 12-18 months from completion of their initial therapy or for patients who are having significant symptoms (e.g., trouble with their intestinal tract, etc). Surgery is not the mainstay of treatment of recurrent disease, but I want people to understand that there are situations in which we will consider surgery in a recurrent disease setting.

Is there a role for radiation therapy in the treatment of recurrent ovarian cancer?
Ovarian cancer is a radiation-sensitive disease; in other words, cancer cells tend to respond quite nicely to radiation. The biggest problem that we have in ovarian cancer is that you have such a large area that you need to treat. The whole abdominal cavity from above the liver down deep in the pelvis is the area that's at risk because as the cancer cells shed from the surface of the ovary, they can float throughout the abdominal cavity and settle down at any point. To effectively treat the vast majority of patients who have disease that has spread to the upper abdomen, you have to treat the whole abdomen. The problem is that many of the normal tissues are more sensitive to radiation than the cancer cells, such as the kidney and liver. Back in the old days, you had what we called whole abdomen radiation (WAR), where you really did radiate the whole abdomen. This was associated with a lot of toxicity, especially gastrointestinal toxicity, etc. But over the years there have been improvements in the ability to give whole abdomen radiation that decreased those toxicities. However, with the advent of better chemotherapy drugs today, there's not a lot of information on where whole abdominal radiation therapy fits in. The other issue with whole abdominal radiation is that it's never been very popular in the United States. It's been much more popular in Canada and if I'm considering it for a patient of mine, I almost always call our colleagues at Princess Margaret Hospital (in Toronto) who have more experience with whole abdominal radiation therapy than just about anybody else. There are a couple of scenarios with ovarian cancer, however, that probably are reasonable to use radiation therapy in a more localized manner. For example, somebody who's had recurrence in the pelvis and undergoes surgery to remove that. The surgeons examine the upper abdomen and the washings, and they know there are no other sites of disease. This is the unusual situation where there's one solid lump that can be taken out. Then you can radiate that area afterward to get any microscopic cells that remain. We'd also use radiation in a patient whose disease does not recur in the abdomen or in the abdominal or pelvic cavity but recurs in the lymph nodes. The lymph nodes are fixed and you can radiate that area. So, yes, under certain situations, we do consider radiation, but it's not part of the routine, general care. Specific patients who have specific disease recurrence patterns, however, are candidates for radiation therapy.

When should you consider clinical trials?
I think it's extremely important to not underemphasize the importance of clinical trials. I think some of the most exciting work in clinical trials is looking at newer agents called "targeted therapy" or "biologic agents". These are really non-chemotherapy type of approaches, but I'm trying to look at things we can use that are analogous to Herceptin® ([MEDLINEplus information about trastuzumab]) in breast cancer that target the cancer cell. Some of the most exciting work that's going on in ovarian cancer and other cancers are improvements in our ability to understand how the cancer cells grow and how to be able to target that, because that's what's different between a normal cell and a cancer cell. If you can target that, and many of these are growth factor pathways and we can use antibodies to block those growth factor pathways, we can use enzyme inhibitors that block those growth factor pathways or we can use enzyme inhibitors to block the effects of those growth factor pathways. An example of that in other diseases that I'm sure many of you have heard about, are agents like Gleevec® ([MEDLINEplus information about imatinib]), which work in different cancers, but really target those cancers specifically. I think that particularly clinical trials with regard to the biologic and targeted therapy hold a lot of promise. The other thing to recognize is that many of the improvements that we have in the treatment of ovarian cancer today are based on the information that we gained from clinical trials. Ten years ago, when we were initially using Taxol in the recurrent disease setting, the responses that we saw in recurrent disease really prompted the incorporation of those drugs into up front therapy and improved the outcome for patients with ovarian cancer. Today, there's a trial going on through the Gynecologic Oncology Group (GOG) that's looking at incorporating a third drug into initial therapy. The drugs that are being used there are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. There's a five-arm study that's being done to try and look at incorporating those third drugs in to see if we can improve that outcome for ovarian cancer (See abstract). That's based on clinical trial information that we've gained just over the last 5-10 years in the treatment of ovarian cancer. I think the next exciting field is the issue of biologic therapy, the targeted therapies where we can try and use these things where the biggest benefit is that they won't have the same kind of toxicities as chemotherapy. It may affect completely different growth pathways and be an effective agent particularly in combination with chemotherapy. So I would certainly encourage people to participate in clinical trials. One of the big problems is that we have so many agents that we can use in the setting of recurrent ovarian cancer, but many patients don't consider clinical trials until they've undergone different treatments, and that's a situation where the clinical trials really limit patients in terms of how much prior therapy they've had. That's really a toxicity issue, I think, as much as anything. I would encourage people to consider clinical trials at all points in their disease process.

Q&A about Angiogenesis Inhibitors

Can you tell us about emerging therapies for recurring ovarian cancer such as angiogenesis inhibitors and targeted biologic therapy?
Although we are talking about therapy in the setting of recurrent disease, the place in which the most impact has been made is not with recurring cancer but with the up front therapies. We're good at getting people into the initial remission. We're just not so good at keeping them there. We're looking at approaches like immune therapies to use in that situation. Although we're talking about recurrent disease, one of the goals of looking at and discovering new agents in the recurrent disease setting is to bring those treatments into the upfront treatment [initial treatment after diagnosis] where we cure patients.

Let's discuss angiogenesis inhibitors first. There are some patients who have tumors that just sit there. That's fine, as long as they're not causing any problems. Unfortunately, most tumors will actually go through a process where they invade. Usually that invasion requires going into a blood vessel. Those tumor cells then will move around and go to other sites and develop metastatic disease. This may not be the best model for ovarian cancer, but what is known is that in the development of metastatic disease, it's not just one cell sitting there. A single cell doesn't cause the problem. What causes the problem is when those single cells grow up and form tumors. With regard to angiogenesis inhibitors, what we're trying to do is prevent those cells from growing up and forming tumors.

The rationale for the use of angiogenesis inhibitors in ovarian cancer is that, in ovarian cancer, there is actually a very unique pattern of spread. For most patients, the biggest bulk of their disease is in the abdominal cavity. We know that in ovarian cancer there has been a correlation made between survival of patients and how vascular their tumor is i.e. the density of blood vessels. The higher the density of blood vessels, the poorer the patients do. So, we know that that blood vessel formation is key with regard to the tumors. It is also known that in ovarian cancer, as in other cancers, tumors will actually secrete growth factors that support the development of tumors.

What kind of agents function as angiogenesis inhibitors?
Actually, the agents that have been in clinical testing the longest are agents that are referred to as the matrix metalloproteinase inhibitors, or MMPI's, and I will discuss those as well as the natural inhibitors of angiogenesis. This article will encompass these inhibitors, and compounds that are specific to vascular endothelial growth factors and a variety of drugs that act through other unknown mechanisms.

What happens when cancer cells invade?
What is known is that there is an entity called the extracellular matrix and that extracellular matrix is a barrier to tumor progression. It acts like a boundary. Tumors secrete these matrix metalloproteinases. These matrix metalloproteinases facilitate the tumors' ability to invade, so you lose that border and the tumor cells can actually invade into the normal tissue. These matrix metalloproteinases also facilitate angiogenesis. They stimulate the formation of these new blood vessels. These new vessels are not normal blood vessels. They're actually very fragile and not as sturdy as the ones we develop on our own. The other thing these matrix metalloproteinases do is they facilitate the ability of the tumor cells to get into the blood vessels and to reach different sites, so they facilitate metastasis. What we know is that if these matrix metalloproteinases can be inhibited, we have the potential to arrest tumor progression. It might be possible to block invasion, it might be possible to block angiogenesis, the new blood vessel formation, and it might be possible to block metastasis.

What are the matrix metalloproteinase inhibitors?
Marimastat is one, a compound made by Bayer, Bayer 12-9566 is one, and another compound made by Ageron, AG-340. The first and last ones are still in testing. We'll cover a little bit about the middle one and then a little bit about the other two as well.

This is actually data from the Bayer company in phase I trials. Patients who were treated with the Bayer drug, Bayer 12-9566, and Johns Hopkins participated in this phase I trial. Remember, patients with a whole variety of diseases will go on matrix metalloproteinase inhibitors in phase I trials. Look at the number of days patients were on these compounds. One patient who went on this trial was on for over a year. She was a lady who had very bulky ovarian cancer. She had a slight response but no disease progression for over a year. Certainly, that's prompted a lot of interest in the Bayer compound in ovarian cancer.

What has come out of the clinical trials?
One of the things is that these biologic agents don't always work like chemotherapy drugs. Medical oncologists who use chemotherapy drugs get used to looking at these in a certain way. We have to keep in mind from a safety perspective that these biologic agents may not work in the same way and we have to be very careful about them. Clinical trials have been done, however, with these agents. One of the clinical trials looked at patients with pancreatic cancer. One of the best drugs for pancreatic cancer is gemcitabine. Having compared it to Marimastat, the researchers found that the responses were equivalent. Patients who had inoperable gastric cancer don't have good treatments, and so in this study, patients who were treated with marimastat or placebo, no treatment, and Marimastat showed superior results. There is some activity with this agent, even in patients with bulky disease. However, and here's the proviso, we need to proceed cautiously, and with some safety. In a study in lung cancer, patients received either chemotherapy alone or chemotherapy with the Bayer compound. Patients who received chemotherapy followed by the Bayer compound had an inferior outcome. We don't know why that happened. At the same time, the NCI in Canada was doing a study in ovarian cancer for women who received taxol-platinum, and at the end of their therapy, they were randomized to either placebo or the Bayer compound. It's a nontoxic compound, so people don't really have any side effects from it. Unfortunately, because of the outcome in lung cancer, this study was stopped. About 300 women went on this study, so there will still be some data, and it will be interesting to see if there's a different outcome in those patients. Because of the concerns from the lung cancer study, this was actually stopped and that drug is not undergoing clinical testing in cancer patients anymore.

What about combining the matrix metalloproteinase inhibitors and standard chemotherapy?
Well, certainly, in animal models, and actually, ovarian cancer is one of the most exciting animal models for this. When you look at the combination of these matrix metalloproteinases and chemotherapy, you see synergy. In animal models with intraperitoneal tumor, when you use chemotherapy, the animals do okay for a while. When you use the matrix metalloproteinase inhibitors, they do okay for a while. But, when you use the two together, some of the animals are cured. This is very exciting, but, as you saw with lung cancer, caution must be used. We have to figure out how to use these agents in combination with chemotherapy. There are phase III clinical trials ongoing to look at chemotherapy and some of these agents. And again, the hope is that the combination may offer enhanced activity in patients with advanced disease.

What about the second group, the natural angiogenesis inhibitors? These are the ones that have been hot in the press, angiostatin and endostatin, which are in phase I clinical trials right now.
Again, phase I are safety trials, so there isn't really have much data on efficacy at this point in time. And again, it is necessary to proceed with caution. Platelet factor-4 and interleukin 12 both function at least in part as angiogenesis inhibitors.

There are a variety of compounds that are antibodies to vascular endothelial growth factor. There's a recombinant human monoclonal antibody to digest that's been tested, there's a compound from the company Fugen, SU-5416, which is not an antibody, but it blocks the VEGF receptor. IFN-alpha, may inhibit release of vascular endothelial growth factor, and there's a Zeneca compound that's actually a bacterial toxin that binds to these fragile new blood vessels that tumors make, and they prevent them from functioning.

There are a whole variety of compounds, and it is not known exactly how they work. Thalidomide is one of these, and a lot of people have heard about thalidomide. There have been numerous studies, none specifically in ovarian cancer, but have included ovarian cancer patients, looking at the use of thalidomide. CAI, which Elise Kohn and Eddie Reed have been looking at out at the NCI, suramin, which is a compound that has had a lot of testing in prostate cancer, and another compound called IM862, being tested at the MD Anderson.

CAI, which is one that was tested most extensively in ovarian cancer, again, is anti-angiogenic and anti-metastatic and has the convenience of being orally administered. At the phase I trial at the NCI, again, phase I, so there are patients with multiple kinds of diseases, it was revealed that half the patients in this study had stable disease. There is an ongoing trial right now at the NCI on ovarian cancer, and the phase I trial looking at CAI plus taxol. Again, phase I, so it's not for any specific disease. So these are some of the ones that have been undergoing research, particularly in ovarian cancer.

So what are the potential applications of these angiogenesis inhibitors in combination with chemotherapy?
The biologics probably aren't going to be very good at shrinking down bulky tumors, but again, with ovarian cancer, there is the luxury with most patients, that at some point in time, they will be in a pretty good remission with low volume and usually nondetectable disease. So the issues are, if chemotherapy is combined with these, can we prevent that last .1% of cancer cells and prevent a recurrence? These could potentially be used as either consolidation or maintenance after initial therapy instead of combining them to use them sequentially. It might be possible to use them as primary treatment for low volume or microscopic disease, and certainly for women who are felt to be at high risk. Maybe ultimately, these will be able to be used as a preventive agent.

However, there are potential problems. When you interfere with the formation of blood vessels, you may interfere with healing. So, certainly after a surgery this is probably not an appropriate thing to use. In patients who have infections and have to heal, these may be problematic. There has been a higher instance of vascular events, blood clots, phlebitis, etc. There's also a concern if blood vessels are blocked; remember that chemotherapy drugs by and large get to tumors by blood vessels, that if you block blood vessels, maybe you'll have antagonism. Maybe you'll prevent the chemotherapy drugs from getting to them. So, again, we have to proceed cautiously in the trials with these agents.

One of the things that we know in cancer cells is that cancer cells have a number of genetic mutations. By and large, the genetic mutations in cancer cells are characterized as oncogenes or tumor suppressor genes. Cancer is highly associated with oncogenes, which are genes that cause cells to grow. These genes are either overactive or in excess. Tumor suppressor genes stop cells from growing. Their loss is associated with cancer.

Bert Vogelstein at our institution elucidates oncogenes and tumor suppressr genes with an analogy of a car: Oncogenes are like the gas pedal in the car, tumor suppressor genes are like the brake pedal. If your gas pedal gets stuck, your car will keep going even though we know that intermittently, your car should stop. These oncogenes activate cells to multiply. Tumor suppressor genes do the opposite; they're analogous to the brake pedal in our car. When tumor suppressor genes are lost, their normal function, stopping cell growth, is lost. In cancer cells, both of these usually occur. There are overactive oncogenes, as if the gas pedal is stuck, and you lose tumor suppressor genes, as if the brake pedal doesn't work. And that's really what happens in cancer. In gene therapies, what we're trying to do is reintroduce these normal tumor suppressor genes. In cancer cells, though, what we recognize is that many of the normal genes in the cell have amplified these oncogenes, which may be targets for therapy.

This scheme just shows you the normal cells. What you can see is that there are a whole variety of these oncogene products, things that you all may have read or heard about. They can be in the nucleus, they can be in the cytoplasm of the cell, or they can be in the membrane of the cell. When they're in the membrane of the cell, they usually have something that binds to them and that transmits a signal to the nucleus that says replicate the DNA and grow. One of the things that we know in these cells is that when you have a growth factor receptor (remember, these are things that stimulate cells to grow) that this is like a lock and key. When you have the lock in the tumor cell and the key comes around, which is the growth factor, it binds and it transmits that signal to the nucleus that says to grow. Not only in some cases do we have extra keyholes made, extra locks made, but sometimes tumor cells will also make extra keys. They'll make extra growth factors and extra growth factor receptors. This is that vicious cycle where a tumor cell can continuously be telling itself to grow over and over again. One of the things we're trying to do is to interrupt that signal.

When we look at ovarian cancer and we look at prognostic factors, there are a bunch of traditional, clinical factors that we all know that are prognostic factors for how patients with ovarian cancer do; the stage of patients, how much residual disease they have, etc. There are also a variety of biologic factors and some of these are growth factors. Her2/neu is a growth factor, epidermal growth factor receptor, (again, a growth factor receptor), and P21. These are all part of that signaling cascade, that growth stimulus signal to a cancer cell. These can be overexpressed in cancer cells and can be a poor prognostic feature as well. This article will point out what we can do to try to interrupt some of these growth signals.

How would we use the signaling molecules as targets for therapy?
The first thing to know is that normal cells can survive without them. If this is going to be blocked, you need to know that your normal cells can continue to function. They should be overexpressed in cancer cells so that there's that therapeutic window. So, when you use these treatments, they're going to be much more effective in the cancer cells and you should know that if you inhibit the signal, cells lose their malignant potential. For example, animal studies or tissue culture studies suggest that when you block this, cancer cells lose their malignant potential. They don't act like cancer cells anymore.

How is signaling inhibited in these cancer cells? How is that message inhibited, that key lock in transmission to the nucleus?
There are a variety of ways. Antibodies can be used to block that surface receptor. You just put something over that lock so that the key can't get into it, and herceptin is a classic example of that. It's an antibody to the Her2neu receptor. You can inhibit the signal within the cell so the message of the membrane that's getting into the nucleus can be blocked. Iressa, which is a compound that is a tyrosine kinase inhibitor, blocks that message from getting to the nucleus. DNA and RNA can be inactivated and antisense molecules are one of the ways of doing that. A compound called ISIS 3521 is one way of doing that. You can inhibit the signal pathways as the cells go through the cytoplasm and farnesyl transferase, which is another whole category of drug that has been looked at in this situation.

Herceptin is a recombinant human monoclonal antibody to the Her2 receptor. When the initial phase I studies were being done with herceptin, they were done in patients with breast and ovarian cancer. Those are two tumor types that overexpress Her2, so they might be targets for these antibodies. However, because the number of breast cancer patients was higher when those studies went on to phase II and phase III trials, they primarily focused on breast cancer. There are, however, trials that are looking at herceptin in patients with ovarian cancer. The GOG has a trial that has been going on for several years looking at herceptin in patients who have overexpressed Her2 and have two or three plus levels of expression. We're looking to see if we can see the same kind of efficacy we see in breast cancer. In breast cancer, we know that herceptin plus chemotherapy is synergistic. When you use herceptin alone or chemotherapy alone, you get certain response rates, but when you put them together you get more than those two that are added together. We also know that, unfortunately, when some chemotherapy drugs, (adriamyacin, for example) are given with herceptin, more toxicity results. Adriamyacin causes some heart toxicity. When you combine herceptin and adriamyacin, you get more heart toxicity, so again, we have to be very careful and make sure this is safe. We do know in breast cancer that herceptin is a very nice drug when combined with paxol and that, again, there is synergistic activity. It can be combined with drugs that we know are effective in ovarian cancer. However, like in breast cancer, this is going to be applicable to only a minority of ovarian cancer patients because not all patients have tumors that express Her2. Originally, if you go back fifteen or so years, it would suggest that about a third of ovarian cancer patients have Her2 positivity. But the GOG trial, unfortunately, is finding that it's only true in about 10%. So this may be applicable to some patients, but we have to ask individually: what do patients' tumor cells overexpress and can we target those cells? This is a way of individualizing therapy for patients.

It's important to understand what synergy truly means. There is a study on an animal model, in which animals are injected with tumor cells and followed over a period of time. A postdoc came in every day and measured the tumor in these animals. Inn the animals that received no treatment, the tumor volume steadily increased. In the animals that received taxol, there was a slowing of the growth. If you go long enough, they get up as high as they did with the control, but there was a delay in the tumor growth. If these animals were given herceptin, the antibody to Her2, there was again a delay in the cancer growth. Nevertheless, the cancer still ultimately grew. If these treatments were given together, however, there would be a complete resolution of the tumors. And that's what synergy means. You get a better effect when you combine these two together than when you add these together. If you replace herceptin with antibodies with epidermal growth factor receptor, and if you replace taxol with platinum, you'd see exactly the same thing. So there's certainly a lot of data to suggest that combining these might be effective.

Please summarize what is known about signaling inhibitors in ovarian cancer
We know that overexpression of signaling molecules is a predictor of poorer outcome. If we inhibit these signals, we might reverse the malignant behavior of cancer cells and, eventually, these cells might die. There are several agents that target signaling molecules that are important in ovarian cancer and are being studied. And these agents, again, may work best when used in combination with chemotherapy. We need to figure out how to do that.

For more information from the NCI, please see Angiogenesis inhibitors and Ovarian Epithelial Cancer

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