Important prognostic factors
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.