A second trial that’s been reported is GOG protocol 114, also an Intergroup study between SWOG and GOG. This randomized patients to IV Taxol/IV cisplatin or a dose-intense approach of two cycles of IV carboplatin dosed to AUC9, followed by IV Taxol and IP cisplatin. This study showed no difference in overall survival. This is not statistically significant, in fact the P value is now 0.11 for this. But a statistically significant progression-free survival, which was not seen in 104. So we have here a slightly different result from a second study that was not really a pure IP versus IV comparison. What we are doing currently is a third trial trying to definitively answer the question. This study is going to randomize patients to either IV Taxol/IV cisplatin or Taxol IV on day one followed by cisplatin IP on day two and Taxol IP on day eight. The reason for giving Taxol both IV and IP is that Taxol is not taken up to any great degree from the peritoneal cavity. So if you are going to get systemic exposure to Taxol you have to give it both IV and IP. This is a tolerable regimen and the study is ongoing. At the current time we have no definitive answer but at least for right now there is not enough evidence in the literature to warrant the use of intraperitoneal therapy outside of clinical trials.
Now what about high dose chemotherapy with stem cell support? The largest data base reported was reported in 2006 at ASCO, 390 women treated over an eight year period and reported to the North American Bone Marrow Transplant Registry. Median age 48, 63% platinum sensitive and overall response rate of 72%. Very impressive, until Dr. McGuire discusses it. What Dr. McGuire did was to take the GOG data using single agent Taxol as a salvage regimen in platinum resistant patients and plot the disease free survival and overall survival curves on the same graph with the survival curves for the high dose chemotherapy. Remember, the high dose population, 63% of them were platinum sensitive, so it’s a better risk population. The red curve is the disease free survival for use of Taxol alone as salvage. The white curve with the big early drop-off is the high dose chemotherapy and there is no place along here that you will see the red curve below the white curve. These are the overall survivals. Taxol is the blue curve on top followed by platinum sensitive high dose chemotherapy, and then platinum resistant high dose chemotherapy. Now this sort of analysis doesn’t prove that high dose chemotherapy doesn’t work. It also though doesn’t support its use outside of clinical trials. We tried to do a randomized phase III trial in the United States. We can’t accrue patients to this because of bias about the appropriate approach. Not everybody, though, believes that high dose therapy ought to be used. About half believe that it’s unethical to use high dose therapy and half believe it’s unethical not to use high dose therapy. So you are unlikely to see a randomized phase III trial come out of the U.S. in the near future. There are ongoing trials in Europe that hopefully will provide us with some answer to this question. But as of right now, there is no clinical rationale to use high dose therapy plus stem cell support outside of clinical studies to treat ovarian cancer.