Robert L. Coleman, MD:The next decision in this process is to try to understand what the optimal therapy would be, and if you look at the various guidelines that are available to us, there are many options. It’s actually a little controversial as to exactly what the best option is. I think the fact that paclitaxel and carboplatin are still the backbone of the therapy that we use today, now more than 20 years since they were introduced into ovarian cancer in the frontline setting, speaks to the fact that this is still a decent backbone. Most of what we have done in the last 2 decades on the research side of things is try to figure out ways to add to this regimen, substitute it for other chemotherapy agents on top of platinum, or figure out different schedulesand all of those are relevant, and all of them make sense.
One of the first things I would say is a common standard of care would be to use paclitaxel and carboplatin with the intent of administering 6 cycles of treatment. The paclitaxel would be administered on a 3-weekly basis, so both drugs would be given once every 21 days. This would be considered a definite standard, and one we have used over and over again.
For the patient who has had an R0 resection, we investigatedalmost the same amount of time ago, 2 decades—whether or not receiving chemotherapy directly into the abdominal cavity would be a better way to deliver the therapy. We’ve done a series of experiments over the last 2 decades to try to isolate exactly what the role was, and it’s unfortunately very difficult to say that we know for sure, in a patient such as this, whether or not they should receive intraperitoneal therapy.
I think many people feel that intraperitoneal therapy is the optimal way to deliver drugs like platinum and paclitaxel, because it delivers relatively high doses of the drug directly to the tumor, and when there’s a low volume of tumor in the abdominal cavity it would make sense. So, there may be this pharmacological advantage in getting the chemotherapy directly into the abdominal cavity.
The trials that we have done are hard to interpret, because they’ve suffered from having different infusion schedules for the drugs that have been administered. They’ve had different control arms, and they’ve had somewhat different findingsalthough, all of the trials that have been done have essentially shown that there’s a very strong progression-free survival advantage, and some have shown at least a strong signal that there may be a survival advantage. But there are caveats in all of these trials, and it’s been difficult for us to settle on the clean recommendation that all patients with a complete resection should have intraperitoneal therapy. There are definitely more side effects associated with it. It’s difficult for patients to receive all of their treatment intraperitoneally, and that seems to be important as far as the benefit that patients received while getting an IP. So, a lot of these caveats do make it difficult to understand whether or not intraperitoneal therapy should be considered.
To add more confusion, we have now experienced some data looking at fractionating the paclitaxel in a large study that was done by the Japanese, where all they did was change the paclitaxel from Q3 weeks to every week during the trial and then use the carboplatin every 3 weeks. This was a very effective method, which produced more progression-free and overall survival in their patient population.
We’ve repeated that trial in the European or Western population with less dramatic results. One of the strategies was to also fractionate the carboplatin, so the patients got weekly carboplatin and weekly paclitaxel. That didn’t really seem to show the degree of benefit that we saw in the Japanese trial. And although we haven’t formally done a weekly versus Q3 weekly paclitaxel carboplatin/platinum study in the United States, we did do one recently that looked at various infusion schedules in combination with bevacizumab, which is a monoclonal antibody targeting VEGF. In that particular trial, called GOG 252, we didn’t see a difference with the IP, and we didn’t see a difference with the dose-downs.
But that is one aspect of therapy that has had some impact on management, and the reason that has had some management on impact is really the result of a different trial, GOG 262, which was taking patients who had suboptimal resections and randomizing them to dose-dense or every-3-weekly paclitaxel with every-3-weekly carboplatin. And in that trial, bevacizumab was allowed as a physician’s choice. So, in the arms of the patients who went on the study and did not get bevacizumab, there did seem to be a benefit in progression-free survival for women who received the dose-dense paclitaxel. The story is not so clear. This option wouldn’t apply directly in this patient, because she actually had an R0 resection, and we don’t have any direct evidence that it would be the best. So, I put it into the category of, “Yes, this is another option for therapy.”
And the last option I want to mention is the use of bevacizumab. We’ve had several trials now: if you include GOG 252 and GOG 262, we’ve had 4 trials using bevacizumab in the frontline setting. 3 have been done in the US, 1 has been done in the European Union, and all of these trials have essentially shownfor the patients outside of the GOG 262—that there’s been this impact bevacizumab can add to the paclitaxel/carboplatin backbone. GOG 218 and ICON7 were 2 trials assessing just that point, and we certainly can get into the details of that in another discussion. What I would say is that both of those trials did show a benefit in progression-free survival without an overall survival advantage. So, the thought is that bevacizumab will also be added to an acceptable strategy in frontline therapy for women who have advanced-stage ovarian cancer.
Transcript edited for clarity.