Important prognostic factors in ovarian carcinoma include age, and one thing to note about age; unlike most other solid tumors, older patients with ovarian carcinoma develop more aggressive disease. The older the patient the more aggressive the tumor is likely to be. The younger the patient, the less aggressive the tumor is likely to be. The reference is a supplement to Cancer in 1992 which summarizes cooperative group data from all over the world. Stage is also an important prognostic factor and perhaps the most important prognostic factor. In fact, this will be the factor that we use to make treatment recommendations. Volume of residual disease in patients with stage III ovarian carcinoma is an important prognostic factor. In early stage disease histologic grade and, as we’ve already discussed, occasionally histologic type is an important prognostic factor. There are beginning to be some molecular biological factors identified as predictive of a poor outcome. Most important prognostic factor though is the FIGO stage, which is shown in abbreviated form here on this slide. Stage I disease is disease confined to the ovaries. This accounts for about 20% of ovarian carcinoma. Stage II disease is disease outside the ovaries but confined to the pelvis and accounts for about 5% of ovarian carcinoma. So roughly 1:4 patients will have what we would call limited or early stage disease. The most common stage at presentation is stage III disease which is spread by direct seeding throughout the peritoneal cavity, or involvement of the retroperitoneal or inguinal lymph nodes. Fifty-eight percent of all patients will have stage III disease at diagnosis. Then finally, stage IV disease which has spread to more distant sites accounts for about 17% of patients. Stage III and stage IV together account for what we call advanced ovarian carcinoma.

Now because this is an intraabdominal disease process in the vast majority of patients, as we’ve indicated, all but 17% of the patients will have disease confined to the peritoneal cavity at the time of diagnosis. Because of that, exploratory laparotomy is an extremely important step in the diagnostic evaluation of the patient and it is also the first step in treatment of the patient. Now I’m not a surgeon, I’m a medical oncologist so I’m not going to try to tell you how to operate on ovarian cancer patients, but everybody dealing with ovarian cancer has agreed on three basic principles for exploratory laparotomy. Number one; the incision should permit the exploration of the entire peritoneal surface. Number two; if there is no gross disease outside the pelvis, multiple biopsies should be taken. By the way, I should emphasize, this slide used to say “multiple blind biopsies”.

One of my surgical colleagues informed me that only interns do blind biopsies. Surgeons always see what they are biopsying so we took the word “blind” out in deference to the gynecologic oncologists. Finally, the surgeon should be prepared to undertake an aggressive attempt at surgical cyto-reduction. Now the basis for this last recommendation is mostly retrospective data in the literature suggesting that patients who start chemotherapy with small volume residual disease have better survival and better response to chemotherapy than patients with large volume residual disease. Until recently we had no proof from a randomized trial of this principle. However we do now. In 1995 the European Organization for Research in the Treatment of Cancer, EORTC, published the results of this study in which they took patients who had been initially operated on and deemed to be not bulk-reducible. They gave them three cycles of chemotherapy. At that time cisplatin and Cytoxan was the treatment of choice. They then randomized them to undergo interval surgical cyto-reduction or no interval surgical cyto-reduction, and then everybody got three additional cycles of chemotherapy. What that publication shows is that those patients assigned to interval debulking surgery – and all were included regardless of whether interval debulking surgery could be accomplished – of those patients assigned to interval debulking surgery there was a statistically significant improvement in progression free survival; 15 months versus 12.5 months, and an overall improvement in survival of 27 months versus 19 months.

The reason you see a discrepancy here between 408 and a total of 299 is that 109 patients had progressed before the end of three cycles of chemotherapy and were removed from study. Everybody who reached randomization point, those who got interval debulking surgery did better. We are in the process of confirming these data now in the United States with this study that will finish up in about a year, that uses Taxol and cisplatin as the treatment but otherwise follows the same design as the EORTC trial. That is, Taxol, cisplatin for three cycles then interval debulking surgery, then three more cycles of chemotherapy; versus simply six cycles of chemotherapy. As of right now, the weight of evidence would suggest that surgical cyto-reduction ought to be done – that’s the weight of both retrospective and prospective evidence – if you are going to do it, the rationale for doing this favors doing the debulking surgery up front rather than in the middle of chemotherapy or after chemotherapy has been completed.

The rationale is to remove resistant clones of cells and to remove large bulky tumor that is poorly vascularized. That is better done before you give your chemotherapy. So right now, the standard of care is up front surgical bulk reduction – and this last statement, as a medical oncologist, I can say this – surgery should be performed by a gynecologic oncologist because they are better at removing bulky tumor.

With regard to prophylactic oophorectomy; there have been publications in the literature, most notably from Buffalo, suggesting that prophylactic oophorectomy in women with positive family histories was indicated. But if you look at their own data published in 1993 in Cancer, what you find is that after prophylactic oophorectomy – and they had a total of 324 women who underwent prophylactic oophorectomy because of positive family histories – their incidence of primary peritoneal neoplasia at a median follow-up of six years was already 1.8% which exceeds the risk in the general population for ovarian carcinoma, and begins to approach the risk in patients with positive family histories. So it would appear that what we are doing here is removing only a small portion of the tissue at risk. Most of the tissue at risk, that is the coelomic epithelium that lines the peritoneal cavity is left in place. The risk of other problems after oophorectomy will increase. So as of right now the only group for which prophylactic oophorectomy is recommended for serious consideration is in those who have hereditary syndromes. And the recommendation was to consider that beginning at age 35 and later. And that came from the Ovarian Cancer Consensus Conference held in August 1994 at the National Cancer Institute. But that was based, as the conference report said, on no data, merely speculation that this would work. So as of right now there is really no truly scientifically defined role for prophylactic oophorectomy. There is a consensus role for those with hereditary syndromes.

Screening for ovarian carcinoma; if you read luminary medical journals like Cosmopolitan and Redbook you will find that screening is something you really ought to be doing for your ovarian cancer patient. What those journals recommend is a combination of pelvic examination by the physician once a year, serial CA125’s annually, and annual transvaginal sonography. But the actual figures on the use of these show that, first of all, pelvic examination has no impact. We know that from numerous studies. When you combine transvaginal sonography and CA125 done in a serial fashion, the positive predictive value for finding ovarian carcinoma is 26.8%, which is really quite good. But, most of those cases are going to be stage III at diagnosis. The positive predictive value for stage I and stage II disease is 9.8% and by most standards a value of greater than 10% is required before you can label an approach as a valid screening test. Not only that, but the studies that have been done to date show that for every one laparotomy that you do for ovarian carcinoma, you are going to do somewhere between 14 and 39 for benign causes that did not require exploration. So there really is a downside for screening for ovarian carcinoma. So at least for right now screening is not recommended, there is no scientific basis for using the combination of transvaginal sonography and CA125 to screen for ovarian carcinoma. There is an ongoing randomized trial that we hope will at least in part answer this question.

Pathologically, coelomic epithelial carcinomas of the ovary fit into four broad categories; serous, endometrioid, mucinous and clear cell. You will note that the two most common types are serous and endometrioid and that’s fortunate, because the two poor-risk types are mucinous and clear cell carcinomas. These two tumors have a much poorer prognosis than the serous and the endometrial types. If you look just at patients with stage III and stage IV disease what you find is less than 10% of the patients have either mucinous or clear cell carcinomas. Almost 90% will have either serous or endometrioid tumors. We don’t know what to do differently for the mucinous and clear cell tumors, currently, to hopefully impact greater on their outcome. So right now that histology has very little impact on how you are going to manage the patient clinically, except to know that the patient is at much greater risk for death due to disease if they have a mucinous or clear cell carcinoma. The only part of histology that really makes a difference in our approach to the tumors is if the pathologist identifies a particular ovarian cancer as being a borderline ovarian carcinoma. That is, it appears to be a well-differentiated tumor with no underlying stromal invasion. These tumors have an excellent prognosis, even if you simply observe them, do nothing to treat them other than an attempt at surgical resection. And even those with intraabdominal spread, that is stage III disease, have an 80% survival at five years. In a large study done by the GOG, no stage I ovarian borderline tumor has occurred as yet at ten years of follow-up. So the treatment for borderline tumors is resection if possible, and then no further treatment until the tumor declares itself as a more aggressive tumor. At that point you would introduce systemic therapy.

In terms of molecular biology, we don’t have a lot of hard information on ovarian carcinoma. Things that you probably ought to take note of are that any mutations of P53 seen in ovarian carcinomas are probably a late change and have nothing to do with etiology. Number two, ras mutations are associated with borderline tumors of the ovary, which we will comment on in just a few moments. And number three, the frequency with which HER2/neu is over expressed is probably considerably lower in ovarian carcinoma than is the case in breast cancer. The GOG currently is running a trial looking at Herceptin ovarian carcinoma. We’ve had to screen 550 patients just to find 25 who are either 2+ or 3+ or HER2 and therefore candidates for clinical trial. And out of those 25 there has been only one responder to Herceptin. So it would appear that HER2/neu is going to be much less of an important factor in ovarian carcinoma than appears to be the case in breast cancer. As yet we have no unifying model relative to molecular factors.

In terms of environmental factors; there are a number of proposed risk factors, none of which have been confirmed. High dietary intake of meat and animal fat has been associated. A high ratio of lactose consumption to red blood cell galactose 1-phosphate uridyltransferase has been postulated. Again not proven. Consumption of coffee, tobacco and alcohol have all been studied. There are some positive reports in the literature but there are a lot of others that deny an association. Then finally, there have been associations reported with industrial exposure, radiation and talcum powder used at surgery. Also mumps. But none of these are confirmed. There are no clear environmental factors that have been directly related to the disease process as yet.

In the area of prevention, there have been four methods proposed; use of oral contraceptives, the use of fenretinide, tubal ligation and prophylactic oophorectomy. And we’ll dispense with these middle two very quickly. There is an ongoing trial in Europe looking at fenretinide and there will soon be a randomized trial in the United States looking at this as a means of preventing ovarian carcinoma, but as yet we have no proof of efficacy. Tubal ligation is associated with a clear reduction in the risk of ovarian carcinoma, and this gets back to what we talked about earlier. That it is reducing the exposure of the peritoneal cavity to external agents. At least we think that’s the case. There is a clear reduction in risk with tubal ligation.

The other two topics have been looked at a good bit more in the literature. First of all, oral contraceptives; it’s clear that a five-year, five consecutive years of use, of oral contraceptives will reduce the risk of nulliparous women to that of multiparous women who don’t use birth control pills. So the use of birth control pills for five or more consecutive years is associated with a risk reduction. The use of birth control pills for ten or more years by patients with a positive family history will reduce their risk to below that of patients who don’t use oral contraceptives and who have negative family histories. The hazard ratio for women with positive family histories who use birth control pills as compared to those who do not is 0.5. A 50% reduction at 10 years, in the risk of developing ovarian carcinoma. Now there are no hard and fast recommendations on whether or not to use oral contraceptives. More importantly, we do not have good studies on the effects of oral contraceptives in those patients who have hereditary syndromes. So we do not know what the impact will be in that specific subset. So any decision regarding the use of oral contraceptives would have to be made in consultation with the patient and would also have to take into account other risks, such as the 1.46 hazard ratio associated with breast carcinoma in the ten or more years consecutive use of oral contraceptives.