Now after you have completed the exploratory laparotomy you can stage the patient in more detail. This is the more detailed FIGO staging system for stage III and stage IV disease. What we’ve added here is a subdivision of stage III disease according to volume of residual disease; IIIa, those with microscopic disease only outside the pelvis, IIIb, macroscopic disease outside the pelvis but no nodule bigger than 2 cm in diameter, IIIc, nodules bigger than 2 cm in diameter outside the pelvis, or involvement of the retroperitoneal or inguinal nodes. The staging system refers to disease as it appears when the belly is open before the surgeon operates. The way we actually look at this disease clinically is to divide these patients into two groups; those who finish surgery with small volume residual disease – no nodule bigger than 2 cm remaining – and those who finish surgery with bulkier disease. According to the SERE in the United States, roughly 40% of all advanced disease patients will have small volume residual disease, about 60% will have large volume residual disease. But if you look just at the patients included in GOG studies, roughly 70% of the patients in surgery with small volume residual disease, 30% with bulky disease. I think it indicates the difference in having a gynecologic oncologist perform the surgery.
As of 1990 the standard of care for patients with bulky disease was a maximum attempt at cyto-reduction followed by chemotherapy. The standards at that time were Cytoxan/cisplatin or Cytoxan/carboplatin. What we want to look at is what has been done in the last nine years, in particular the last one to two years. There have been three themes that have dominated clinical research during the last decade. The integration of Taxol in to front line therapy, the choice of a platinum compound and the optimum dose of schedule of the drugs that need to be used. With regard to the first of these, the introduction of Taxol into front line therapy; there have now been four major randomized trials completed and reported. The most recent in May of this year at ASCO. GOG protocol 111, EORTC NCIC OV10, GOG protocol 132 and ICON-3. We want to look very briefly at each of these four.

GOG protocol 111 was the first of the studies to be published. This was published in the January 4, 2006 issue of the New England Journal of Medicine. This study took patients with large volume advanced disease, randomized them to receive either Cytoxan/cisplatin or Taxol as a 24 hour infusion followed by cisplatin with each regimen being given every three weeks for a total of six cycles of therapy. If you read the publication you know that in regard to the five major parameters looked at, Taxol/cisplatin was statistically superior to Cytoxan/cisplatin. Overall response rates, 73% versus 60%. Clinical complete response rate, 51% versus 31%. Percentage of patients grossly disease free at second-look laparotomy, 40% versus 24%. Median progression-free survival, 18 versus 13 months. Median overall survival 38 months versus 24 months. We now have follow-up out to nine-plus years and those differences continue to be maintained.

In 2006 at ASCO the results of the confirmatory trial was presented, this was OV10 a European/Canadian study. There are several differences in this study compared to the GOG study. Number one, patients with both large and small volume disease were included. Number two, the Taxol was given as a three hour infusion. Number three, up to nine cycles of treatment were allowed, and most patients did receive more than six. As an aside I should add that what the study also demonstrated was that you do not want to use three hour Taxol with cisplatin because there is an unacceptably high rate of significant neurotoxicity, either grade III or grade IV. That’s been demonstrated not only in this study but in two other trials that used three hour Taxol with cisplatin. What this study did was essentially reproduce the GOG study. In terms of overall response rate, Taxol/cisplatin was superior; 77% versus 66%. Clinical complete response rate, 50% versus 36%. Median progression-free survival, 16.6 versus 12 months, and median overall survival 35 versus 25 months.