I'd really like to welcome everyone. This is, I hope, a record year for the Survivor Course. Let me give you a little bit of background. This course is obviously for you. This whole meeting is for you, but this specific session is directly for you. This course sort of has evolved over the last couple of years. We used to do alternative medicine and so on, and many of the patients complained that that is not what they wanted to hear. They wanted to hear from the experts, that is, people on the cutting edge of treatment for ovarian cancer, and so with several of your help this year, and Alice Spinelli, MSN, ARNP, Dr. Powell, and Dr. von Gruenigen we've designed this format. I would encourage you to be critical of this format and you can e-mail me or Karen Carlson of the GCF with your suggestions so that each year we can make this course better. I also would like for it to be somewhat interactive. It is not a huge group, and I would encourage questions and audience participation.

I would like to acknowledge a few people; Dr. Fowler who is the head of the Gynecologic Cancer Foundation (GCF) and really is supporting this academically in every way, and Aventis Pharmaceuticals which is financially supporting this course.

At this time I guess I would like to get going. The first speaker of the day is Ted Trimble of the NCI and he will be talking about clinical trials. Oh, and I left out Alice Spinelli, President of the SGO.

I am delighted to be here with you. I am here to talk about clinical trials relative to ovarian cancer. You should have a copy of my handout here, which will reduce the number of notes you will have to make. I do want to emphasize our web sites that we have. Cancer.gov is the main National Cancer Institute web site; Cancer.gov on clinical trials is a good web site to find out about all of the trials that are sponsored by the National Cancer Institute. And finally 1-800-4-CANCER is our main cancer information number, and the people who answer that phone can also help give you some information about clinical trials.

I've divided the talk up into the four big topics: Can we prevent ovarian cancer? Can we find it early? How can we cure it? How can we maintain quality of life during and after treatment?

In terms of prevention studies we know that we need to do a lot more to understand the biology of early ovarian cancer. One of our projects is conducted through the Early Detection Research Network, led by Dr. David Fishman at Northwestern University in Chicago. He is doing a small Phase II trial in which women undergo laparoscopy and a scraping of the ovary, which he calls an ovarian pap. We don't know if this is going to work as a screening method but it is something we are examining. In addition, we are sponsoring some small Phase II trials in women with high inherited genetic risks with ovarian cancer who plan to have their ovaries removed. They receive three to six courses of an agent, generally a pill taken by mouth, and then they undergo removal of the ovaries to see if that helped decrease precancer changes in the ovary. There is one such study being conducted at Fox-Chase Cancer Center, also through Gynecologic Oncology Group, and another small study being conducted at MD Anderson in some of our ovarian spores. Another question is, what is a protective effect of removing the ovaries and tubes in women with high genetic risks for ovarian cancer? We have some data from retrospective studies suggesting that it does protect against most cases of ovarian cancer. There does seem to be some risk of developing a primary peritoneal cancer, but we really don't know the accurate data on that. And, also although we know it does affect quality of life to remove the ovaries, we don't have hard data on that. So, we have started a new trial within the last month looking at about 800 women. This is being conducted through the National Cancer Institute and the Gynecologic Oncology Group following women who undergo surgery to remove ovaries and tubes to see how that affects quality of life and how that affects the risks of developing ovarian cancer or primary peritoneal cancer later.

Ted Trimble: Generally premenopausal. The standard of recommendation is for women to consider it by age 35 or when they completed their families. But, the risk of ovarian cancer and/or breast cancer in these families continues up to age 80 or 90, so we do see postmenopausal women undergoing it, but I think the majority of them are premenopausal.

In terms of screening studies, we have a number of big studies underway. The first is the PLCO study. It is a large trial involving 74,000 women. Even so it is not quite big enough as a definitive evaluation of screening ovarian cancer. The primary end points are looking at screening for lung cancer, and colon cancer in these women which are much more common cancers. But for the ovary part of that women are randomized either to a regular exam or a yearly Ca-125 and ultrasound for six years, and they are followed for an additional four years. So, we are going to see if those tests help detect ovarian cancer early, and also we are putting together a serum bank which will be tremendously useful to evaluate new markers. That trial has completed accrual and we are now just following that group of 74,000 women, but we really won't have any data for another eight to ten years on this.

Audience: Any consideration to the new ultrasound approaches?

Ted Trimble: No, not in that study. It is kind of a bare bone study being done with ultrasound that everybody in the community has. So, no.

Now Dr. Ian Jacobs in the United Kingdom has also opened a large study with 100,000 postmenopausal women. They're randomized either to an exam or to two screening algorithms. The first is based on a personalized level of Ca-125 developed by Steven Skates at Harvard. So they identify the normal range of Ca-125 for each woman, and if that goes up then that person undergoes an ultrasound. And on the third arm they are screened with ultrasounds with Ca-125 as backup. That study has just opened in the United Kingdom. . In the ROCA study, which is being organized by Steven Skates, it is initially 2,000 women at high-risk for ovarian cancer who are being followed with that individualized Ca-125 every three months.

Audience: How do you define high-risk? Are these women who are tested positive for BRCA 1 and 2?

Ted Trimble: Either they have been tested and are positive or their family history suggests that they have at least a 20 percent life-time risk of developing ovarian cancer.

In terms of trials in early stage ovarian cancer, we know that accurate staging is critical. When we've looked at patterns of care studies in the United States, relatively few women with early stage disease undergo that accurate staging. Unfortunately, the studies that we have done in this country show that chemotherapy after surgery does not appear to prolong overall survival, but it can delay recurrence. Long-term survival without recurrence is about 80 percent for women with Stage I disease, and 70 percent for Stage II disease. We are currently working hard to try to identify those women who will benefit from chemotherapy, and those who do not need chemotherapy after surgery. At the current time we think we are probably giving a lot of chemotherapy to women with Stage I disease who do not need it. We aren't smart enough yet to figure out who's going to benefit from it.

In terms of trials in advanced ovarian cancer, we know that effective surgical staging and debulking are critical. The standard of care has been six to eight courses of intravenous carboplatinum, and paclitaxel (Taxol). We don't know whether we should continue the Taxol as consolidation therapy, because the woman's body is generally able to tolerate more Taxol. We don't know if it makes sense to give it. We do not know whether we should add additional drugs with other mechanisms of action, although we think we may be able to cure more people if we try other drugs. And we are not quite sure when we should consider intraperitoneal therapy. There are three trials now suggesting survival benefit associated with giving chemotherapy into the peritoneal cavity, but it has not become standard of care. It is a little harder to give, and it has a few more side effects.

Long range questions that we are very curious about are whether we can characterize each person's cancer, and then individualize therapy. We know that there are different responses to therapy. We know that cancers in one person are different than cancer in another, so we really want to be able to characterize each person's cancer and individualized therapy. There is some exciting work coming out of labs at the University of Michigan, National Cancer Institute and Memorial Sloan-Kettering describing how we might be able to characterize those cancers. Then we need to know how we can combine traditional chemotherapy with new biologic agents.

In terms of current Phase III trials in women with advanced disease. I just want to give you an overview of what is going on across the world. The National Cancer Institute of Canada, and the European group, which is the European Organization for Research and Treatment of Cancer, is looking at the addition of topotecan to our standard of carboplatin and Taxol. That same group has looked at epirubicin, which is similar to doxorubicin, to see if that helps improve survival. The French/German group together with the Scandinavians are currently studying carboplatinum, paclitaxel and gemcitabine (Gemzar). And then the biggest trial underway is one that was developed as an international study between the GOG in the United States, a group in Australia, New Zealand, United Kingdom and Italy. They are looking at a five-arm study of carboplatin, Taxol with or without topotecan (Hycamtin), gemcitabine (Gemzar) or liposomal doxorubicin (Doxil). It is a 4,000 patient study. It is the largest study ever undertaken in women with ovarian cancer and they are about half-way to completing that trial.

To identify new drugs, what we generally do are Phase II trials in women whose cancers are either, resistant to platinum and Taxol or sensitive to platinum and Taxol. We separate those into two different groups because obviously what we've learned is that if cancers are sensitive to platinum and Taxol then they are more likely to be sensitive to new drugs, and less likely to develop resistance. If they are resistant, then they are harder cancers to treat. We are obviously more interested in drugs that are active in patients with resistant disease. That is how we identified Gemzar. We have learned that we have to separate those trials in to two different groups. We've also learned we're most likely to see if a new drug works in women who are active, have a good performance status, are up and about, and who have had fewer different treatments. If someone has had five or six different treatments then we are less likely to see whether that new drug works. So we do tend to restrict our eligibility for trials to women who are both active and have had fewer different treatments. In Phase I trials of new drugs we are trying to figure out best how to give the new drug to avoid the toxicity. We generally do not have restrictions on the number of prior treatments, but we do, again, hope to find people who are relatively active so that we have a better sense of whether the drug causes problems in terms of toxicity when we give it.

And finally, how can we maintain quality of life? What we have learned as the most important thing is to ask about quality of life. A lot of doctors may not ask, and a lot of patients may be too scared to ask because they are just concentrating on treating the cancer and they may not feel comfortable saying that I have symptoms and what can be done about it. We know that we have to treat the symptoms optimally in terms of treating pain, nausea, anemia, fatigue and depression. We have fairly good treatment for all of those. We still don't know best how we can avoid neurotoxicity, particularly "chemo brain" or the "pins-and-needles" feeling that we see fairly commonly when we use cisplatin. It is less common with carboplatin. But we can see it with both carboplatinum and Taxol.

Finally, how can we strengthen intimacy and social support, which we know are essential for quality of life, and also in some cases we think, can help prolong survival?

I have a few slides on how someone can participate in ovarian cancer research. The first is going over family history, finding out whether other people in your family have had breast cancer, particularly early breast cancer, the combination of breast and ovarian cancer, or the combination of colon cancer, endometrial cancer and ovarian cancer. If you have a strong family history it is important to get evaluated at a cancer center active in cancer genetics research. And, if your family history suggests that you have a high-risk of ovarian cancer, about a 20 percent or more life time risk, then we think it is important to sign up for a cancer genetics registry and one of the screening studies that I mentioned.

If you chose to undergo removal of tubes and ovaries as a precaution, then I would encourage you to sign up to donate tissue for research because that tissue is extremely important. And, if you have a high-risk of ovarian cancer, I would encourage you to ask your other blood relatives to sign up for a cancer genetics registry. We have new legislation that is coming active later this year concerning patient privacy. If for example, you come from a strong family history with ovarian cancer and have a sister, we are not allowed to contact your sister just because you give us your sister's name. Your sister has to contact us so that we can include her in the study. If you have to undergo surgery for a potential ovarian cancer, obviously I would encourage you to make sure a Gynecologic oncologist is available. You should ask if you can donate tissue removed at the time of surgery for research, and after surgery ask if you are eligible for any clinical trials.

Audience: On the program they have vaccine trials listed. Have these trials started?

Ted Trimble: Yeah, Dr. Khleif is going to talk about vaccine trials.

And again, after you finish treatment ask if you are eligible for any clinical trials. We do have some clinical trials of some consolidation therapies after treatment. If your disease recurs, ask if you can donate tissue for research. Again, ask if you are eligible for any trials. You should encourage other women to consider clinical trials. You should also encourage your doctor and hospital to be active in clinical trials. About half of the Gynecologic oncologists in the U.S., are active in clinical trials, but we would like all of them to be active in clinical trials. And, it is also important to encourage society to be supportive of clinical trials. Some health departments have not been supportive because they think it costs them extra money to participate in clinical trials. Some insurance companies have not been supportive of clinical trials. It has gotten less common because of a lot of educational efforts that the SGO and NCI have done, but we need to continue the fight to make sure that clinical trials are available.

At present about 2 percent to 3 percent of women with ovarian cancer go on NCI-sponsored treatment trials. This is about the same percentage for other adult cancers. This does not include women going on company-sponsored trials, or trials at cancer centers. This 2 percent to 3 percent are just those trials sponsored through one office at the National Cancer Institute. So the number may actually be higher, but it is probably not more than 5 percent. Certainly the NCI, the Society of Gynecologic Oncologists and the Gynecologic Cancer Foundation are doing a lot to promote clinical trials through our web sites, development of educational materials; brochures, videos and public service announcements, and outreach to community hospitals and to international partners to help promote our trials.

So that ends my slide show. I would be happy to answer any questions. I have to leave shortly, so I won't be around for the discussion. So please ask questions now.

Audience: You mentioned getting tested and registering for a genetic registry. Have there been any changes to legislation to protect patients who go through genetic testing, and register for something like that?

Ted Trimble: I will ask David Gershenson at MD Anderson to comment on that.

David Gershenson: I think it has been a concern, but realistically it's not a problem according to genetic counselors and people who will do this at our institution. Essentially, I think that all 50 states save one have instituted a genetic protection act saying you can't use genetic testing as a deterrent to discriminate against people from insurance standpoints.

Audience: Would that one be Louisiana?

If you find that occurring you need to report it to the insurance agency. Now the problem with the life insurance, they can ask that, but that is a whole different thing, but actually health insurance they cannot.

Ted Trimble: Let me ask Ann Kolker to comment.

Ann Kolker: I was just going to say that a lot of states have enacted legislation and that federal legislation is pending.

Audience: I have a question regarding resistance. You had mentioned that choice of subsequent therapy might have been related to sensitivity versus resistance to carbo/Taxol, and I know every resistance testing in the past has not been very effective in terms of determining what drugs to use? I am wondering about progress, if there has been any advancement in resistance testing in terms of its usefulness in choice of chemotherapy drugs?

Ted Trimble: Some of my panelists may want to comment on this. There are some standard tests for resistance; we often will use them if a cancer becomes resistant and we are able to obtain tissue, but we don't use it generally as part of the decision on primary therapy. Research in the laboratory is beginning to let us know what are the genetic changes in a cancer initially, and what are those changes as that cancer becomes resistant. Once we fully understand those genetic changes then we could help to design new drugs for those changes, but we're not quite there yet.

Audience: When you speak of resistance you're mainly talking about just the people's response to therapy?

Ted Trimble: Exactly.

Audience: I have a question. If someone is contemplating surgery as a precaution because they are high-risk, did you mention an agent?

Ted Trimble: I mentioned some studies where we were giving an experimental agent to women who are undergoing prophylactic surgery. What drugs are under study? One of them is a retinoid agent called 4HPR and the other is a progestin.

Audience: Could someone recommend an institution that would be interested in receiving my genetic testing information? I had a BRCA 2 variation of uncertain significance and the laboratory that conducted the testing is not interested in any information, such as the fact that I have ovarian cancer and I've reached age 30.

Ted Trimble: To a certain extent it depends on where you live, and we have very good cancer centers with interest in genetics all around the country. Again, I would just call 1-800-4-CANCER, and they will direct you to one of the cancer centers with strong interest in genetics. Where do you live?

Audience: I live here, and my call to 1-800-4-CANCER lead to six other phone calls.

Ted Trimble: I think maybe MD Anderson maybe one of the closest.

Dave Gershenson: Karen Lu at MD Anderson institution is the one who does the ovarian screening, high-risk and certainly I'm sure she would be happy to talk to you. If you have a problem call me.

Ted Trimble: We have a cancer genetics network that ties together a number of the major genetic registries so that we can pool data on, let's say different BRCA 1 and BRCA 2 mutations.

Audience: How do we know what happens in the community to ovarian cancer patients?

Ted Trimble: NCI does sponsor a database that covers about 16 percent of the U.S. population. That is the SEER database. In addition, the Congress has given the Centers for Disease Control money to help all 50 states to set up more accurate tumor registries. Some of the states are further ahead than some of the others, and so that data is not as accurate as we would all like it to be. Cancer registries are very expensive, and you have to make kind of a commitment as a society to do them. In the Netherlands and Scandinavia when you are born you are issued a health identification number, and they track that. So every time you fill a prescription, every time you go to the hospital they have that information. They can track all their citizens and know what surgery they've had, what drugs they are prescribed, and know what their diagnoses are. In Scandinavia and the Netherlands they have much better population tracking systems then we have. As I said our system only covers 16 percent of the country, and we have no way to track people if they leave the state that is part of that tracking system. Other questions? Thank you very much.