What about carboplatin? There have been three trials internationally looking at carboplatin. A British study comparing AUC6 to AUC12. A Danish study comparing AUC4 to AUC8 and an Austrian study comparing cisplatin to a combination of cisplatin plus carboplatin. Again, no advantages to increasing the dose intensity of the platinum compound by escalation of carboplatin dose or by its addition to cisplatin. So it would appear, based on this, there is no reason to go above an AUC of 4 with carboplatin.

What about Taxol? Well Bristol-Meyers Squibb funded Johns Hopkins to do a metaanalysis of the first five phase II trials of Taxol in ovarian carcinoma. That was presented in 2006 at ASCO by Eric Lewinsky. What that showed was that there was an improved response rate with an increasing dose of Taxol up to a dose of 175 mg per meter square every three weeks. Beyond that there was actually a decrement in response for each additional 10 mg per meter square increase. We’ve had two randomized trials looking at this issue, one comparing Taxol 135 per meter square to Taxol 175 per meter square; 15% response rate with 135, 20% response rate with 175, not significantly different. Then another study comparing 175 to 250, a GOG trial, with response rate going from 27.5% at 175 to 36% at 250. No difference in progression-free survival and no difference in overall survival. If there is a dose-response relationship with Taxol, the slope of that curve is not steep at all but the slope of the toxicity curve is dramatic. So the best evidence we have today would appear to suggest that there is no reason to go beyond 175 mg per meter square of Taxol. So these would represent reasonable dose levels for these three drugs. You may want to ask, “Well, gee, why did you put 60-70 per meter square and why did you put AUC 4-5 when you’ve shown evidence for 60 and 4?” Well, it’s that little bit in me that got trained that said more is better. I just can’t let go of it. And neither can anybody else. So the data suggests that we certainly don’t need to go to higher levels than these because all we do with that is increase toxicity.

What about Taxol schedule? We really don’t have hard data on a lot of this yet but I think that what we do know about Taxol schedule is the longer the infusion the greater the myelosuppression. The shorter the infusion the greater the non-hematologic toxicity. In fact with the longer infusions you don’t see cumulative toxicity with Taxol but with the shorter infusions you do see cumulative non-hematologic toxicity. The optimal schedule is not known. Either a three or 24-hour infusion is preferred right now because we have a lot of data on those. As of yet we don’t have any conclusive proof that a weekly one hour schedule is acceptable, although I know that a lot of you probably use that. And as of yet we don’t have much in the way of data in a 96-hour infusion, which is actually being tested in a randomized phase III trial now. Because, at least in breast cancer, there are some reasons to believe that a more prolonged infusion might be better and the preclinical data supports that. But right now either the three or 24-hour infusion, either one, would be a reasonable approach to the use of Taxol in ovarian carcinoma.