Let’s look at the drugs that would be chosen as alternative therapy. First there are a group of four drugs that have been shown in published studies to be active in patients who are platinum resistant by the definitions I showed you; Navelbine, about an 18% response rate in platinum resistant patients, tamoxifen, 13%, ifosfamide, 12%, and 5FU leucovorin 17%. All of these responses are in the mid-teens but there is some activity. The better group of drugs though are those drugs that have been shown to be active in Taxol/platinum resistant patients, resistant to both of those agents. These include oral etoposide, which has the highest raw response rate in patients with Taxol/platinum resistant disease, 32% in a GOG trial. Eight responses among 25 patients. Topotecan has a 13% response rate in Taxol/platinum disease. Doxil a 19% response rate. If you went to ASCO you saw a study presented showing 23% that had 63 patients on it. The full data base has 110 patients in it. It was collected by a pharmaceutical company which is now Abbott, and the overall response rate was 19%. Gemcitabine 14% response rate in Taxol/platinum resistant patients. My own personal order of choice here is oral etoposide as the first salvage. If and when they relapse after that, Doxil and then topotecan in that order. Though both topotecan and Doxil have FDA approved indications in ovarian cancer, etoposide is in the compendium as a salvage drug but the problem with oral etoposide is you have to go through the durable medical equipment provider to be reimbursed. So it’s a little more complicated, though I have never viewed pills as durable medical equipment. So that’s the situation with regard to salvage therapy.
Right as the last thing I want to comment very briefly on dose-intensive approaches like intraperitoneal therapy and bone marrow transplant. What we are looking for is a second threshold on that dose-intensity curve. We’ve shown you evidence that the dose-intensive curves flattens after a threshold of roughly 60 per meter square for cisplatin, AUC5 for carbo and 175 per meter square for Taxol. With these dose-intensive approaches we are looking for a second threshold. Because of time I will go through these quickly. There have been two randomized trials looking at IP therapy as front line therapy. The first was published in December of 2006 in the New England Journal of Medicine. This is Southwestern College Group, GOG Intergroup study, randomizing patients to IV Cytoxan/IV cisplatin, versus IV Cytoxan/IP cisplatin. That article will tell you that this makes intraperitoneal therapy the treatment of choice for small volume residual disease. It does not. The study was flawed. The accrual was extended to 650 total patients. The original goal of the study, a hazard ratio of 0.67 was never reached. There was a difference of 49 versus 41 months median survival favoring IP therapy, hazard ratio of 0.77. But the study really gave us a counter-intuitive result because the 0 to 0.5 cm subset, the subset we thought would benefit the most because it had the smallest volume of disease, actually didn’t benefit. Benefit was seen in the larger nodule group which doesn’t make any sense. So for that reason this study served to keep the issue alive.