Speaker: Larry Copeland

Again, I would like to thank the organizing group, Dr. Mutch, and GCF for the opportunity to speak. It is challenging to say something meaningful in ten minutes as you've seen from the prior speakers, but I am going to try. I want to disclosure conflicts of interest. I have done a lot of consulting for a lot of different companies over the past couple of years and I just want to put that up front to begin with a slide show.

My talk is going to be very brief in three areas. One is drug development as it relates to the GOG, and then I'm going to give you an example of a new drug that is currently in development in the GOG. I'm going to give you an example of a new targeted drug delivery concept that is at the earliest stages of development, really in private industry at this time. And, this is kind of the GOG mechanism slide shown. The new drug method of development is really run by the developmental therapeutics committee and Mike Bookman leads this effort and really does an excellent job. So they essentially have a Phase I committee, Phase II committee and they go through promising drugs that are coming out of animal studies and get them in to the clinical arena to evaluate both toxicity and efficacy, and then as these drugs are developed they are passed on to the site committees, in this case the ovarian committee for incorporation in to treatment, either front line therapy or for recurrent disease.

So in the Phase II studies we have a number of protocol lines that we run. In ovary, we run four lines, platinum resistant, platinum sensitive, biologics and intraperitoneal. The intraperitoneal group has not been active for some time. And again these slides are courtesy of Mike Bookman's effort, as is the development of this science. This reviews from 1996 to current, platinum resistant drugs that have been tested and I've tried to highlight some of the ones that are currently being tested. Taxotere, the Rowe study showed some activity. Keep in mind these are platinum resistant patients. They are the toughest patients to develop and these are additional studies that are under development, additional drugs. The 186C is the drug that I'm going to come back and talk a little bit about, Xyotax or CT2103.

This is the platinum sensitive queue, and as you can see we are challenged here to identify active drugs. In general, if a drug shows activity in the 20 percent range or higher then we consider it a drug that needs to move on to further investigation. And, again these are the drugs that are under development, and I know that Dr. Gershenson is going to talk about a few of these specifically. So, I am not going to dwell on these.

This is the biologic queue, some of which have been covered by Dr. Mueller, and again it's just a sequential queue of evaluating promising agents.

The next part of my talk is to talk about Xyotax (CT-2103). This is a novel taxane and the GOG currently has opened 186C, which is a Phase II study for patients with recurrent disease, and the Phase I study (Xyotax and carboplatin in combination) is on the verge of opening. This is GOG-9914, and this will evaluate the dosing of Xyotax with carboplatinum. Assuming that we demonstrate appropriate safety and activity, this will then move to a Phase III trial up against Taxol/carbo, which is our current standard therapy, and this will also include consolidation.

So what is Xyotax?

Okay this is a Xyotax molecule and it has a tagged on glutamic acid polymer, and there are some potential advantages of this. It's engulfed in the cell and then the enzymes within the cells cleave off the polymer, essentially activating the drug. So it is kind of a Trojan horse mechanism. With this activation, these enzymes in general are over expressed in cancer cells and so it is kind of a targeting method. It is not broken down in the blood stream so it is water soluble. It doesn't have to be dissolved in a solvent that causes hypersensitivity reactions, and so it has a number of potential advantages including some quality of life issues. Alopecia appears not to occur, or if it occurs it is very minimal. The neuropathy is less of a problem. I already mentioned avoiding hypersensitivity, avoid premedications and the infusion duration can be much quicker. It is administered over ten minutes instead of an hour or three hours. So it does have some potential advantages and this is a Phase II study done at Memorial Sloan-Kettering by Sabbatini and colleagues. There were 43 evaluable patients. Xyotax was dosed at 175 every three weeks, and as you can see in the platinum sensitive group it had some modest activity. This is a very heavily treated group of patients. Some patients have had as many as nine prior therapies. So it is very heavily pretreated, platinum resistance, and a number of these patients have also already seen Taxol, so it is a real challenge for new drugs to come up and show activity after Taxol/platinum failures now a days. They were certainly able to tolerate it receiving between 3 and 14 cycles. Okay, that is all I'm going to say about Xyotax.

The next is folate receptor based therapy, and this is a company out of West Lafayette, Indiana, called Endocyte, a small company. They are trying to take advantage of cancer cells over expressing a special receptor, a folate receptor. These folate receptors actively transport whatever is attached to the folate molecule into the cell. And so this is just a diagram of such. Now folate is a normal substance, and folate normally goes into the cell through a simple transport mechanism. But, in addition to that there are folate receptors that are over expressed in various cancer cells. These folate receptors are active transporters to whatever is attached to them. Now as it turns out ovarian cancer over expresses these folate receptors more than any other tumor, 90 percent. Now you heard about molecular targeting earlier today, Her-2-Neu, like a 12 percent expression, P53, none of them come close to 90 percent. So in terms of targeted opportunities the folate receptor may be special. The brain also has a very high folate receptor expression as does endometrial cancer, and then it falls off pretty quickly after that with regard to expression at other tumor sites. But, the ovary perhaps is a special opportunity, and this is just an immunoperoxidase staining of the folate receptors and the brown staining reflects the positivity of the folate receptors in papillary serous carcinoma of the ovary. Now in a normal ovary we don't get these folate receptor expressions. In mucinous tumors of the ovary, folate receptors aren't expressed; however, in serous and metastatic tumors there is significant over expression of folate receptors.

Now this company is trying to find a product to kind of get going. They are in development. They are essentially being funded predominantly by venture capital people. They're targeting three areas of interest. They are using folate as a scan for diagnostic imaging. They are using the folate receptor to try to immunize the cells and to get an immune response and they are using folate to attach chemotherapy to like Taxol and get it into the cells specifically through that method. They are in Phase II for the diagnostic. They are starting Phase I just this quarter and preclinical with chemotherapy.

This is an example of the folate scan. This is normal. The kidney's collecting system has folate receptors so they show up. They were concerned about kidney toxicity and this has not proved to be a problem. In this patient with advanced stage disease, you can see that she had a technetium and it lit up all over the place.

Now with regard to the immune status, what they do is they immunize the patient with some kind of an agent, flourascene, and then the patient will react to anything that carries flourascene, and then they tag flourascene onto the folate and inject it. This is an example of the folate showing up as antigens in these mice tumors in the liver. These are some mice studies and this is survival and this is the control mice that died very quickly--non-targeting immunization and then with the folate targeted immunization process they had a 100 percent survival over a short period of time.

Besides going into preclinical studies, Phase I studies should begin this year. The three sites that have been identified so far are Santa Barbara, Indiana University and Baylor. They anticipate Phase II studies starting in 2004.

And this is kind of the last of the folate targeted chemotherapy and this is attaching folate to Taxol and this is the control group. This is tumor growth, not survival. This is tumor growth here on the control, and then the untargeted drug. That is just Taxol by itself. And then the combination treatment where the Taxol is attached to the folate and picking up the advantage of targeting folate receptor positive cells.

That concludes my talk. Hopefully I was close to my ten minutes. Thanks a lot.

Audience: What are the criteria to enter into the folate study?

Larry Copeland: The folate immune study? Right. Patient with recurrent ovarian cancer I believe. I have not seen the protocol, but I know that Indiana University, Santa Barbara, and Baylor are the three sites that have been identified so far. My knowledge of this company and the product is fairly superficial. I was actually invited to go over and visit the company by venture capitalists and I kind of got picked up, flown over, got two or three hours of presentation, and then the venture capitalists wanted me to give them some feedback as to the long term potential of their product. They were kind enough to e-mail me some of their Power Point slides that I could use. It's just a very small company, it's in very early development. I just want to give you an example of one of the novel concepts that people are working on in terms of trying to get things going.

Audience: What was the name of that company?

Larry Copeland: Endocyte.

Audience: The company is at Purdue University?

Larry Copeland: The Ph.D. that is leading the science is a Ph.D. at Purdue. The company is in a separate building though. They're private, but they are supported by the scientific network out of Purdue.

Larry Copeland: Dr. Pierre wants to know the name of the venture capitalists?

David Mutch: Any other questions for any of the other panelists? We have a few seconds left here.

Speaker: David Gershenson

Thank you, David. I also would like to thank David and the organizers of this meeting for the opportunity to speak to you this morning, as well. I told David that it was pretty impossible for me to talk about new drug development without speaking about molecular based therapy, and so some of what I'm about to say will duplicate a little bit of what you've already heard, but I'm going to speak specifically about some of our trials at the other cancer center in Texas.

You've already heard about what targeted therapy is. It constitutes therapeutic approaches aimed at bypassing or correcting specific molecular defects responsible for aberrant biologic behavior of cancer cells. What do we target? The ideal target is a gene that is either over-or under-expressed in cancer cells compared with normal cells. Or it is one that is malfunctioning or is absent in cancer cells. And this is not a comprehensive list, but a list of possible targets, and again you've already heard about a number of these and I will talk again specifically about a few of them.

First, the growth factor receptors. You've heard about Her-2-neu. I'm going to mention E1A and Herceptin, which Carolyn mentioned. There had been a trial with Herceptin that showed a fairly low response rate of less than 10 percent and whether or not combining Herceptin with chemotherapy will be an advantage. I don't think we yet know. Epidermal growth factor you also heard about and I will also talk a little bit about that, as well as the tyrosine kinase targets for the drug Gleevec.

First, a little bit about a gene-therapy study that was based on a gene product from an adenovirus developed at MD Anderson by Mien-Chie Hung, and this is the E1A gene therapy. This gene inhibits the growth of ovarian cancer cells that over express the Her-2-neu oncogene. But we also know from most recent studies that it can work on cells that don't over express the Her-2-neu oncogene. Unfortunately early studies told us that about 30 percent of ovarian cancer cells over express Her-2-neu, but we now know that that's only probably about 10 percent based on immunohistochemistry. So in this Phase I study of the E1A gene therapy, an intraperitoneal catheter was placed and the E1A was given intraperitoneally. This was a weekly injection three times and then the patients had one week off and it was repeated. In this study we did find that a few patients did respond. I already mentioned that further experiments showed us that the E1A gene therapy worked not only in Her-2-neu over expressing cells but those that didn't over express Her-2-neu. We are planning a follow-up Phase I trial that will combine E1A gene therapy with chemotherapy, Taxol. That study should begin within the next two to three months.

You've heard about the epidermal growth factor receptor. We know that approximately 50 percent to 70 percent of ovarian cancers do over express epidermal growth factor receptor and there are several new candidate drugs that you've already heard about. One of these drugs is C225, which is a monoclonal antibody to the extra-cellular domain of EGFR. Another drug is Iressa and there are some other drugs related to Iressa, that target the intracellular tyrosine kinase domain of EGFR. Studies in other types of cancers, i.e. lung cancer, have shown potential benefits of combining chemotherapy with one of these agents. We plan to begin a study, this is a multicenter study at Fox-Chase Cancer Center, Memorial Sloan-Kettering and MD Anderson, using the C225 drug in combination with carboplatin and Taxol in patients with advanced stage, newly diagnosed ovarian cancer.

Carolyn also mentioned Gleevec. It's a drug that has worked wonderfully in chronic myelogenous leukemia, because of its specific mutation. It does work on these tyrosine kinases. Whether or not it will be active in ovarian cancer, we do not yet know. We are currently conducting a Phase II trial of Gleevec in patients with platinum-resistant recurrent ovarian cancer. We know that approximately 70 percent to 80 percent of patients based on our studies, as well as studies from elsewhere, do over express one of these three targets, C-kit, Abl or PDGFR. This is an oral therapy and the most common side effects that have been observed to date are GI toxicity, nausea and vomiting, edema or swelling or weight gain, and fatigue. And, of course, it can also affect blood counts. It is too soon to know whether Gleevec is going to work. To date in our study we have already treated nine patients, and there are two other studies - a GOG study that you heard about from Larry Copeland, and another study at the NCI.

What about drug resistance pathways? Proteosomes are a mechanism for cells to transport things out of the cell, and so it often works overtime in cancer to transport chemotherapy out of the cell before it can actually be active. Proteosomes are increased in many cancers. Again, they move chemotherapy out of the cell before it has a chance to work, and there is a new agent called PS341. It's a new treatment that aims to inhibit the function of these proteosomes and overcome chemo-resistance. Pedro Ramirez, one of my associates at MD Anderson, will be beginning a Phase I/II trial with PS341 plus carboplatin in patients with platinum-resistant ovarian cancer within the next few weeks. Again, this will combine this agent with chemotherapy and the hypothesis is that this agent will overcome drug resistance.

Tumor suppressor genes. These are genes whose loss of function allows unchecked growth of cells, and you already heard about P53 or BRCA 1 and 2 from Carolyn, Michael and others. Judy Wolf did a Phase I trial of P53 gene therapy at our institution as Carolyn has, and again, this was laparoscopic placement of a catheter with instillation of the P53 on a daily basis for five days; this was repeated every three weeks. All the patients in this trial were platinum and Taxol resistant. There were 17 patients in the study. Two of the patients who were enrolled were never treated, for the reasons you see there. And, all but one of the patients had high-grade serous carcinomas. These are the toxicities that we observed in this trial. They are what you might expect - fever, chills, fatigue, myalgia, muscle aches, nausea and abdominal cramping. There were some responses in patients who received two or more cycles of this P53 gene therapy and there were nine of these patients. Two patients had a partial response. There were four patients who had stable disease over three to four cycles of therapy, and three of the patients had progressive disease. Judy is planning in the near future to begin a Phase II trial of P53 gene therapy.

Antiangiogenic therapy. I don't think anyone has talked about this too much today. In order for a tumor to grow, it must have a blood supply. And once it reaches a certain size, it tends to start to overgrow its blood supply. So, it has to secrete factors that will help stimulate new blood vessel formation, and that's what's called angiogenesis. We think that inhibiting this process of angiogenesis can inhibit growth of a tumor. We know that from preclinical studies and models that the tumor can make substances that stimulate blood vessel formation and these are the secreted products interleukin 8, Basic FGF and VEGF, which is a vascular endothelial growth factor- and by blocking these substances, tumor growth is inhibited. In these preclinical studies with mice, alpha-interferon at a biological dose, not the maximum dose, was found to inhibit the secretion of these substances. So, by using pegylated alpha-interferon, which is a long acting interferon that will act for about a week, at a low dose, they found that tumor growth could be inhibited in the mice. So we are now translating this into a clinical trial using the same equivalent dose for humans that was used in the mice and looking for decreased expression of these angiogenic factors. This clinical trial will therefore test the hypothesis that low-dose continuous exposure to this alpha-interferon acts as an antiangiogenic agent in ovarian cancer. We think that about 80 percent of patients will over express one of these three angiogenic factors, IL8, Basic FGF or VEGF, and this is the design of the trial. Again, patients with platinum resistant ovarian cancer over express at least one of these three factors and are treated with pegylated interferon at escalating doses on a weekly basis. We then evaluate the effects on the markers in the blood that we originally measured.

So what is the future of ovarian cancer treatment? Again, you've heard from almost every speaker that ovarian cancer is a genetic disease. We just don't really yet understand all of the genes involved in the pathogenesis of ovarian cancer. As a group, you've heard that we believe that the molecular characterization of ovarian cancer, prior to any therapy, will allow us to better individualize therapy. So it's not just a shotgun approach treating everybody the same. I think the hope really is in targeted therapy. Whether or not targeted therapy would be best used in combination with chemotherapy or by itself, I don't think we yet know, and that is going to depend on the agent itself. Thank you very much for your attention.

Audience: We've heard some of the presenters say that ovarian cancer is a genetic disease. How does that shape-up in regards to all cancers?

David Mutch, MD: All cancers are genetic.

David Gershenson: All cancers are genetic. The slide that I showed says, "cancers."

Audience: Is the vaccine available for the general public?

David Gershenson: No, this is only as part of a clinical trial.

David Gershenson: Soon.

Audience: Do you know anything about the relationship of cancer and the pH of the body?

David Gershenson: I don't know if there is any relationship between the pH of the body and cancer.

David Mutch: I also don't know anything. I know that there have been some studies and people are looking at the relationship of pH in the abdominal cavity to ovarian cancer, but I don't have any specific information about it.

Audience: I just want to know referring to the Ca-125-- you know the levels. I know that when first diagnosed with ovarian cancer that the levels are high and this is a target later on while you're under treatment and all. What happens when the Ca-125 is normal and yet you still have cancer? Why isn't the Ca-125 elevated?

David Mutch: So the question is why is the Ca-125 often not elevated in ovarian cancer?

Speaker: The Ca-125 is like other markers. Tumors are not homogenous in general. In other words ovarian cancer is not ovarian cancer. So some ovarian cancers have some, for example, P53. Everybody talked about P53. Only a fraction of ovarian cancers have P53. It is exactly similar to Ca-125. Some ovarian cancer patients were shown that their tumor secretes Ca-125 and therefore it could be used as a marker or target for therapy. But, the biology of the cancer really differs from one patient to another, dependent on probably the genetic background of the patient, probably the way the cancer developed.

Panel: 80 percent of ovarian cancers express Ca-125. But, that illustrates why Ca-125 is not a good marker for early detection, because it only detects about 50 percent of Stage I patients or patients with early disease that is very treatable and curable. I think that obviously everybody is looking for different markers. So through proteomics, genomics, hopefully we will discover markers that may be used in combination with Ca-125. I mean Ca-125 is not bad, but it's not a great marker.

Audience: Are there any tests now for early detection for either beginning or return cancer beside Ca-125 that are available?

David Mutch: The question is, are there other potential tests of early detection for ovarian cancer? The answer is yes. There's a proteomic test, which you may have heard about, coming from the NCI, but that's not available yet. It still needs to be tested in the general population.

Audience: Just to summarize. For individual markers there has been a long of effort going on for probably 10 to 15 years to improve on Ca-125 without, I think, a tremendous amount of success. The newer technologies would suggest that we might be able to break that logjam by using proteomics and also by looking at a whole spectrum of proteins that may be detectable in the blood of patients who have early ovarian cancer. My only caution is that these are new technologies, they need to be developed, and most importantly, from my prospective, they need to be validated. The worst-case scenario is we approve and get out into the market a test that is not accurate. We are not going to do anybody a favor. So that is actually ongoing right now.

Panel: I could add to that. Actually at GOG now we have two studies, one for ovarian and one for cervical cancer, where basically we are going to be looking at proteomic profiles for the response of different patients to cancer. But, again I stress, these are very, very early, and they're not going to be used for the general public very soon before they are very defined.

Panel: If I could just add another thing to that too is that the general approach to proteomics is to look for a pattern. At least for the NCI group. Ultimately the identification of those proteins may also then become potentially vaccine targets; they become targets for therapy, so on and so forth.

Audience: What is the difference between resistant cancers and sensitive cancers?

Panel: These are arbitrary definitions that have been created based on observations that the longer until a recurrence after you've completed primary therapy, the more likely you are to respond again a second time or maybe even a third or fourth time to a platinum drug. And so, these definitions were formulated somewhat arbitrarily and six months is used as a cutoff; meaning, that if you recur within six months of completing primary chemotherapy you're "platinum resistant," and if you recur later than that time you're platinum sensitive. Also if you progress on primary treatment, your tumor progresses, you're platinum resistant. So, the definitions have been set-up. They are not absolutely perfect by any means, but that is what we use. That is the language that is commonly used in trial development in ovarian cancer. I don't know if Larry wants to say anything.

Larry: I think that is even being extended now because there is another term being used, "extremely sensitive," and extremely sensitive is if your disease-free period after primary therapy is more than twenty-four months. So it is essentially how well you respond to front line therapy. If your response was very short, less than six months, you're resistant, over six you're sensitive, and that keeps going on. If your response is over a year you're probability of re-response is higher than six months, two years is higher, and three years is even higher. So, the longer you sustain your response the more sensitive we call you. It's just arbitrary terminology.

David Mutch: What basically it means is if you respond to the therapy you're sensitive. If you don't respond then you're resistant.

Panel: If I could just add a comment on that. In terms of the new biology of the disease and a genomic approach, you may see in the next five years a rewriting of that kind of an approach. As David said, it is sort of a retrospective analysis. If you respond you're sensitive, if you didn't you're resistant. The goal is to look at gene expression patterns of the primary tumor when you get operated on. Basically, chop through that data and then say okay, here we have a profile that says this patient will respond to Taxol, or this patient will not. So, we will know up front and hopefully tailor the therapy to the patient.

Audience: My question concerns consolidation therapy. If you're in remission and you're on consolidation therapy, is there any study or thought on how long to continue that, consolidation therapy?

Larry: Yes, consolidation therapy is a source of significant controversy amongst the experts in the field. GOG-178 was a study done in concert with SWOG and the study was closed early as it was interpreted as a positive study. There are critics, and essentially it was a seven-month progression free survival superiority for patients that got twelve treatments of Taxol and consolidation versus three. For nine cycles of therapy they were stable for seven months. And the question is, "is this a pay me now or pay me later type of situation? And, would you have gotten that same seven month benefit by just having stopped the therapy and reinitiated treatment at the time of recurrence?" I think as we see more therapies being developed for molecular targets that are nontoxic, I think you are going to see more interest in maintenance therapy or consolidation therapy. I think it is being called more often maintenance therapy rather than consolidation. It's kind of the attitude out there that ovarian cancer has this analogy with diabetes. With diabetes you keep giving insulin and the patients do well for a long time. With ovarian cancer there's got to be some type of insulin potentially that we can also use to keep them stable for a long period of time. So there is interest in it. There is also a lot of controversy. I think we are going to see studies being conducted focusing on maintenance.

Panel: I think I would agree with Larry. We are just in our infancy in terms of developing this concept. There is only one reported trial as Larry mentioned. It's a flawed trial. We don't really know. Even the experts don't know how to interpret the results exactly, and so I think you're going to see a whole flurry over the next few years of consolidation trials with molecular agents, with chemotherapy, with high-dose chemotherapy. We just launched a trial comparing normal dose chemotherapy to high-dose chemotherapy within a randomized trial. So, you are going to see a lot of different strategies used.

Audience: It still seems like, to a great extent, we go back to trying to get more people into more clinical trials to come up with the answers to all of these questions that you've all raised. I guess as people in the lay community what can we do to help this happen?

David Mutch: I think that the first question out of a person's mouth should be, "is there a trial available for me?" Not necessarily that they will choose that trial, but they ought to hear about it. If it fits them and they want to go on it then they should. Or, "what trial is available?"

Audience: They should hear about it without having to ask I would think. Your responsibility always falls down on us, and a lot of people don't know.

David Mutch: If you're treated in an academic center, then I think that there are going to be trials that are open, and sometimes in private practice groups there are going to be trials that are offered to you. You're right. We do need to do a better job educating physicians about the availability of trials, and about how important trials are. But, we will have a long way to go both ways.

Panel: There is reference made to the academic medical center. Certainly private practitioners participate in clinical trials as well. We are all in academic centers. We are not here saying that academic centers are necessarily the only place to get treated. I think cancer is serious enough that I would encourage more patients to get second opinions right up front, because there are many options and they expand very quickly with second opinions. In terms of seeing what is available, second opinions, I think, are very valuable.

Audience: How come we don't hear of radiation as a treatment for ovarian cancer? I'm just curious.

Panel: Radiation historically has certainly played a role in ovarian cancer. There were kind of various centers where it was used more than others. Certainly, Princess Margaret in Toronto had large trials with radiation. MD Anderson-we conducted large trials with radiation. It's kind of fallen by the wayside but there is some potential interest in it I believe. There's such a strong bias against it at the present time, it's hard to image that it's going to inject itself back into clinical trials to any significant degree at this time. Certainly the combination of chemotherapy and radiation is being reconsidered. Part of the problem with radiation for ovarian cancer is a peritoneal disease, and patients are often subject to at least one, and quite often multiple surgeries. If there's one thing that doesn't fit with radiation, it's multiple surgeries. One of the end stage problems we deal with in ovarian cancer is bowel obstruction and one of the serious sequela of whole abdominal radiation is bowel obstruction, it's kind of inherently not something we want to jump on too quickly.

Audience: I went to the OCNA conference in September in Washington and I believe there was a speaker there from the NCI who talked about the new blood test coming, its accuracy in the early stage, and he made it sound like, boy it was coming in three years or so. Now today I'm getting the impression that, whoa it's still so early on, it's long to come.

Panel: Well three years is a long time. The test has just hit the scientific community. It was published just recently and it is very difficult to just say it's going to be here tomorrow. Is it possible in three years? Yes. I don't think that that is out of the question. But, definitely not next month. People are doing lots of verification studies. Including our NCI team, to just make sure that this is happening properly, correctly with the proper controls. It could be possible within three years.

Audience: Well at that time it seemed as though they were asking for more participants in the trial, whether it was women in remission or high-risk women. Is that still happening?

Panel: Yes. This is part of the verification phase. Clearly more trials need to be done in this. If your question is whether it's going to be like Ca-125 to be used as a marker, or it's going to be like PSA for detection or something, this is different. It is still going to be within clinical trial use for at least the near foreseeable future.

Audience: Eventually it could be part of a woman's annual exam, like a pap smear? That was my impression.

Panel: Yes. The answer to that question is, yes, eventually it may be, after all these verification phase trials are done to make sure it is going to be helpful, and it's going to be proper to be used.

David Mutch: One of the problems with ovarian cancer. In the study that was done the prevalence of ovarian cancer in that study group was 50 percent. Half of the patients had it that they knew of. So, the test looks really good. But, in the general population the incidence of ovarian cancer is going to be more than 2,500 or 1 in 3,000 people. The tests have to be very sensitive in order to pick that up. If you have a bunch of false positive tests like the Ca-125 then you could do more harm than good.

Panel: I would say the issue frequently for screening is specificity, not necessarily sensitivity, though sensitivity is critical. In that initial study the specificity was especially good, but it is still to the point that if you went to the general public because the prevalence of the disease is so low, you would be operating on a lot of women who might not have cancer. Now, the follow-up study from what I heard is that the specificity has gotten even better. They may be reaching it. But as Dr. Khleif says, time is relevant to everybody. They are moving very fast but they need to do large validation studies. We are talking about thousands of specimens to make sure that it's going to accurately diagnose the disease, and that is why they are going out to the community very aggressively and saying, "please, if you want to donate your blood in a certain way we could use it." We will keep it blinded. We will run it through the machine and we will be able to get the data that we need to hopefully make it a marketable exam.

Audience: First I would like to applaud the panel of great scientist. It appears to me that everything we hear is on the horizon. It's in the future. That is why we are here, to support the future, because without us the future is not as bright. My question is, if a hereditary factor could be factored in younger women considered as high-risk and then prophylactic removal of the ovaries be recommended, then why not recommend this to another category of women. In my opinion, from what I've studied, and I've only studied a few, I've learned that postmenopausal women on HRT for longer than ten years are equally at high-risk, given the fact that most ovarian cancers, I think the number is 65 percent of them, are discovered in postmenopausal women. Then why not after menopause, start the Ca-125, and if it is only 50/50 then go ahead and prophylactically remove the ovaries? Why can't you do it with a laparoscopic surgery? My wife has undergone two major seven hour operations. I think it is ridiculous that it wouldn't have been done prophylactically.

Carolyn: I think it's very difficult, to number one, say that everyone should have their ovaries out after menopause. And that is basically the benefit that has to be balanced when you look at the risks of the surgical procedure and the complications that occur from that. I mean we are all blessed that a lot of our patients don't have complications, specifically from their surgeries, but when you start doing it in the thousands, those 1 in a thousand complications that can be devastating will come up. So you really do have to target your recommendations for patients who we know are at risk. Now, a lot of information evolves over time. A lot of the genetic assessment is just about a decade old, and so identifying patients, getting good family histories, getting good genetic studies, and then making recommendations where the benefits would outweigh the risks are happening better and better as physicians get educated and patients get educated. Similarly with hormone replacement. This information is evolving, and so we are better apt now to look at patients at a little bit more of an increase and again weigh out those benefit risk ratios. That is an individual thing and for every single patient the benefit risk ratio has to be done. Surgery may be far more risky than the actual perceived risk of cancer in that individual.

Audience: What are the risks of a laparoscopic removal? And after menopause what good are they anyway?

Carolyn: The risk of surgery can be very different from person to person. In other words, if someone had a long history of hypertension, the stress of anesthesia may be significant, the risk of a heart attack or a stroke on the table just during any kind of general anesthesia or general procedure should not be minimized. So again every single individual has to be evaluated. Laparoscopic procedures are not without risks. The trocars are inserted blindly. Vascular injuries can occur. Bowel injuries can occur. And again, even in the best of hands these things happen on a 1 percent risk. We have those complications happen every now and then and they can't necessarily be predicted beforehand. So, when you ask what is the risk of a laparoscopic procedure, it's very, very variable from person to person. You have to take everything into account.

What good are the ovaries afterwards? Well, I don't think we actually know what else postmenopausal ovaries do except not make estrogen. Are they completely worthless? Well I don't know. You have a room full of women, I would ask them to respond to that as well.

Audience: I hear a lot of negative things about taking Premarin. I'm a young woman and I have no choice, I have to take it and everything I read about it is bad. Hormone replacement is bad, but again I have to have it. So, what do I do?

Larry Copeland: Well we have ten minute talks and you're asking a three hour question. The question is, "what are the risks of Premarin?" It's been used for a long time and there appears to be a fairly reasonable safety profile for Premarin or estrogen replacement therapy. The epidemiologic risks have come to light with the Women's Health Initiative last year when they closed on the combination of estrogen and progesterone. This was in like 5,000 women and they had increases of 10 or 20 bad events. Breast cancers were up a bit, but colon cancers were done. That was probably a tradeoff given the prognosis of those two cancers. There were some vascular events, increasing heart attacks, increasing strokes, increasing DVT's, but there was only 20, 30 or 40 patient difference in 5,000 women. There is very little information that went along with that. Were these women on aspirin? Did these women have some diseases that pre-existed to clotting problems? There are a number of hypercoagulable states. So, the study was very incomplete in its data.

The other thing is the average age of patients going on that study was about 63 or 64 or 65. Very abnormal times to be intervening with hormone replacement therapy. You normally would be considering intervening at age 50 or onset of menopause. It could well be that these women in their 60's had ten plus years to develop vascular disease, and then you add in a little factor of minor hypercoagulation, which in a 50 year old wouldn't have been a problem. In these 65-year-olds it blossomed. Personally, I'm pretty critical of the study. I don't like the study. I think there is probably hundreds to thousands of women in the United States who have come off hormone replacement therapy. They are not deriving the benefits from it. These women are miserable off the therapy. The spouses are miserable because the wives are miserable and it has presented a very difficult and challenging issue. Now my comments are kind of cancer aside. There are some cancer issues that need to be considered as well in that. The Women's Health Initiative Study, I don't much care for. I think it's too bad they closed it. I would have liked to have seen some more long term results and some further explanation as to why the patients, perhaps, had those complications other than the fact that they were just on the medication.

Audience: If a patient has widely metastatic disease would they still be eligible for the trials at MD Anderson, NIH or any of the other trials?

Panel:

Panel:

Audience: Why is it that physicians seem to misdiagnose?

Panel: Could you speak up a little. I can't hear what you are saying.

Audience: I was talking about my wife. Our first experience was, what she went for we didn't know it existed in her. We went to the doctor the first time and he suggested that it was gas, and then the next trip it was decided that maybe we would have a further examination. And so, all of the sudden this tragic thing happened. Basically, healthy, so to speak. She had never been to the doctor one time. Healthy, feeling good, having lots of fun. Then, all of the sudden this happened. I was concerned because especially if she had waited five more days. It would have been too late, and I've constantly worried about this. Here I've had the fortune of visiting a session like this Finally, I ask this question. Why is it that doctors have such a problem in diagnosing the reason or the reasons for the problem? Maybe some of you can answer this. Maybe this is worse because I am a total layman in the medical community. Maybe the question has been answered.

Panel: I think the issue is very important. Clearly, the earlier diagnosis of any cancer the higher the probability of a successful outcome. The Gynecologic Cancer Foundation, and the Lay Ovarian Groups have focused on this as a major issue very appropriately, and I hope very effectively. It's one issue for us to sit here and say, "well it was obvious her symptoms were ovarian cancer," but I guess you have to empathize and go to the primary care physician who is seeing a lot of patients. Out of a hundred patients that have gas, one of them may have ovarian cancer. Is the onus on them to move on and do Ca-125 and vaginal ultrasounds in every one of them? You know they have to use some clinical judgment. I think there is greater and greater awareness. Ovarian cancer clearly is a challenge with the subtleness of its symptoms. But the symptoms are pretty clear. Nevertheless patients can be totally asymptomatic and be in the process of developing advanced disease. I think groups like this carry this message as effectively as anybody. We agree with you.

Audience: Hello everyone. I just have a quick announcement. I'm Katherine Clark. I am a family physician and I am a 2 ½ year survivor of Stage IIIC ovarian cancer. I am making a documentary film. A lot of you already know about it. The film is an artistic and spiritual venture, but I'm also interested in other people's stories. It is very personal. It is a personal story, my life story. I am also interested in other life stories and that is why one of the things I'm doing this weekend is filming other ovarian cancer survivors. I'm looking for women who are interested in participating and telling their stories. I'm interested in illustrating a range of different kinds of women, of different ages and ethnicities, with different kinds of ovarian cancer, perhaps. I'm just interested in hearing what happened to you and how you are living with this, and how you're living your lives and how it's transformed your lives. Also, what is good about your lives as well as what's difficult about your lives. So, I'm here all day today and tomorrow with a professional camera person. We are very ambitious. We have funding. We have pharmaceutical companies that have committed to funding this project. We are aiming for television, public television, perhaps HBO and movie theaters for this next fall or early next year. So it is a highly profession project and I'm interested in your participation. So come talk to me if you might be interested. I'm also giving out posters.

What? The name of the movie. My name is Katherine or Kasha. My nickname is Kasha. The name of the movie is The Kasha Project. That is the current name of the film. That is the working title. So come and talk to me. I'm staying at the Hilton Garden Inn, Room 511. You can feel free to call me over there. I will be around here at the luncheon and I can give you my information. I'm on a cell phone. I can give you my cell phone number if you want to get in touch with me as well. If you want my cell phone now I can give it to you.