DR. HOWELL: I was absolutely delighted to see Jerry put that equation back up there, because the basic principles of IP chemotherapy are often forgotten.

You want a drug that has a very difficult time getting out of the peritoneal cavity but, once it gets out of the peritoneal cavity, you want it gone from the systemic circulation very, very quickly.

In the very early days, we took another strategy to try to improve on that equation, or try to utilize that equation to improve IP cisplatinum, and that is, we used sodium thiosulfate.

Sodium thiosulfate reacts fairly quickly with cisplatinum in the systemic circulation, and what we wanted to do was to make the half-life of cisplatinum in systemic circulation shorter.

So, we ran a lot of sodium thiosulfate into the systemic circulation at the same time that we ran 200 milligrams per meter squared of cisplatinum into the peritoneal cavity.

That worked. We didn't get extra toxicity in the systemic circulation. We got an additional increment of relative exposure for the peritoneal cavity and the systemic circulation.

Sodium thiosulfate is still around. It is being developed to prevent hearing loss in children receiving cisplatinum.

So, it represents another opportunity to improve on the basic pharmacokinetic principles of intraperitoneal cisplatinum that haven't been fully exploited.

I would caution that that pharmacokinetic principle doesn't cover the whole story. What we are really doing is, we are trying to say, look, we can get a certain amount of drug to the tumor if we give it intravenously.

If we put some more drug on top of a tumor nodule, maybe we can get some more diffusing from the free surface into the tumor, and get an incremental additional amount of drug into the tumor.

Yes, we probably do that work. Work by Eric Loss from The Netherlands Cancer Institute demonstrated you get a little bit more, 1.5 fold more drug or so, to very small tumor nodules.

It is interesting to me that that small incremental addition is probably what accounts for the improvement in disease free survival and overall survival here. So, we didn't have to deliver a lot more platinum to the tumor to get this bit of benefit.

With novel drug delivery systems that were mentioned -- nanoparticles, other strategies for getting platinum drugs to tumors -- the opportunity for a substantial increase in the amount of drug getting to the tumor is really just now beginning to emerge.

I would caution that antibodies intraperitoneally violate that basic principle. Antibodies often have a hard time getting out of the peritoneal cavity, but they also tend to hang around in the systemic circulation for a long, long period of time, bevacizumab in particular.

So, while there may be real antitumor advantages to controlling VEGF in the peritoneal cavity, antibodies generally don't diffuse from the surface of a tumor into the tumor very well, and they stay around in the systemic circulation too long to be applied with great power using that pharmacokinetic principle. Thanks.

DR. ARMSTRONG: I wonder if either of you want to respond before we take another question.

DR. ALVAREZ: I think he made some excellent points. I guess the other thing when I think about intraperitoneal chemotherapies, is that they are to look at changing the tumor micro-environment, particularly with respect to immune response, et cetera, that may be an additive over and above what we see with the pharmacokinetic advantages of drugs that actually kill cells.

DR. HOWELL: One particularly important point is the issue of whether bevacizumab, given IV or IP, would change permeability coefficients in the tumor, both in the rate of movement from the vascular compartment into the tumor, and from the peritoneal cavity into the tumor.

DR. ALVAREZ: There has actually been a recent study looking at the inter-tumor pressures and the interstitial pressures with respect to the ability for monoclonal antibodies to penetrate tumors, and how that is altered, to some degree, by a variety of different strategies.

DR. BOOKMAN: I just wanted to point out that, in spite of 1,000 women being enrolled in phase III trials and a lot of development work that has been done, I want to underscore the comments that were just made, that we don't know why this works, we don't know if it has anything to do with direct drug penetration, or if it is a consequence of changes in the tumor micro-environment.

We haven't really done studies as these patients have been treated to address any of those questions. I am hopeful that, as new trials are considered, that really we try to understand better how it works.

We may be chasing after the wrong goal. We may be thinking it is really all about giving more platinum directly on top of the tumor, when really it is something completely different.

DR. THOMAS: I guess that begs a couple of really basic questions that I think everybody needs to think about. Number one is, do the results of these studies with IP therapy suggest that all future trials must have an IP standard arm to which a new therapy is compared?

I think that is something we need to throw out. While the comment was made that, when we have level one evidence, it is never ignored, in fact, we have many, many suggestions in medical literature of very good level one evidence that has not been taken up because of problems such as IP catheters, or chart radiation, where radiation was supposed to be given on Saturday and Sunday.

So, I would like to bring everybody back to that question. Are we at a place now where these data are so strong that any new therapies must be compared to an IP strategy? If so, as Mike has pointed out, we don't know which part of that strategy worked.

Was it the Taxol dosing? Was it the IP route? Someone told me I would be laughed at for saying route. So, let's try and struggle with some of these issues, because this is how we are going to move on to the next generation of incorporating these new agents into phase III trials. I would like some comments.

DR. MARKMAN: I find this discussion fascinating. We have three prospective, randomized control trials, all of which have shown a substantial survival advantage. The most recent, an increase in median survival of 17 months. We are questioning this.

I remind everybody that yesterday or two days ago the FDA approved the use of Tarceva in pancreas cancer, with a median improvement in survival of less than two weeks.

I would submit to you that, in the next several weeks, there will be more advertisements to oncologists around the world, or at least around the country about that, than will be seen about these extraordinary results in the next 10 years.

These are economic issues. There is no incentive for an oncologist to give IP therapy. I have been in meetings in the last year, where the data are known, where 80 to 90 percent of oncologists said they would not even present the data to their patients. I think the advocates should know about this.

There is not a pharmaceutical company that has the slightest interest in advertising any of these data. We have a prospective randomized trial that has looked at quality of life that shows that, at 12 months, there is no difference between the two arms.

Yet the data are ignored. This is a very serious problem. The NCI is going to do its part. It is going to have a clinical alert that is going to come out and unless someone speaks up, these data will again be ignored.

This is not an issue of toxicity. There is no increase in death. The randomized trials were performed by Cooperative Groups that have community oncologists.

The first trial was, in fact, done principally by SWOG, which is a bunch of medical oncologists added to by the GOG. This can be done. There is no economic incentive to do it and there is no company interested, and those are the facts.

DR. AGHAJANIAN: I agree with Maurie. This can be done. We treat all our optimal ovarian cancer patients with IP therapy. It is doable. If you give the patients the choice, they choose the treatment that will let them live longer. Again, I think the barrier is financial. There is no financial incentive to do this therapy.

DR. ARMSTRONG: Carol, just because you and I are both at institutions where we have adopted that as our standard of care over the last few months, I think the other thing, to be perfectly honest and fair, in those situations, that involved a lot of work with administrators, people who control hospital beds, outpatient treatment, training nurses, et cetera.

As Maurie says, it is not something that necessarily financially gives you something back, but if you believe the data, it is something that you are willing to do to try and get the infrastructure set up.

It does take some time to do that. I think there is no question about that, and I know that, even in talking with folks today, the question has been, you know, do we have the infrastructure, are we training GYN oncology and medical oncology fellows about how to do those types of treatments?

Those are things that really, I think, as training program directors, et cetera, we have to be thinking about those as well.

DR. AGHAJANIAN: I don't think that is fair to women with ovarian cancer, to not offer them a therapy that will make them live longer, because it takes some time to set up some infrastructure.

DR. ARMSTRONG: I agree. I think that people's hesitations are because the infrastructure doesn't exist. If you want the infrastructure to exist, you are the people who have to make it exist at your institution.

DR. TRIMBLE: I just wanted to take this opportunity to ask a question. As we are preparing the clinical announcement regarding the use of IP therapy, one issue which Dr. Mark Clanton, who is our Deputy Director, raised was whether reimbursement was an issue.

There is a CPT code for administration of chemotherapy via an IP route, and I just wanted to ask whether anybody in this room in the United States has had problems with reimbursement for IP chemotherapy.

DR. AGHAJANIAN: We have had no reimbursement problem with any private insurer or Medicare.

DR. MARKMAN: Ted, important to point out, that is not the problem. The problem is, it takes a whole day to do this and you get paid for that treatment.

If you administer weekly chemotherapy for an hour, and you have 10 people you can do that, you can do the math, and see what an individual practice makes.

It is not the reimbursement for this. It is the lack of reimbursement for something else. The economic disincentive here is incredible, plus there is no drug rep coming into your office daily, maybe hourly, telling you how great this is. These are facts. These comments are meant for the advocates. We need to have you hear this.

DR. OZOLS: I would be curious to know what the clinical alert is going to say about what dose and what drug combination to give.

In GOG-114, Maurie's study, the conclusion that was studied said that this combination should not go forward because of the toxicity. I haven't seen what the conclusion is from the last study. I haven't seen the publication. I just wonder what the outcome of that study is and what the recommendation is going to be.

I mean, I don't think we can minimize the toxicity. Twenty percent of the patients had grade three and four neuropathy. This is a toxic treatment.

Nobody is arguing with the results of that study. They are spectacular results. The question is, as I think Mike Bookman asked, what is the reason for that? Is it just the catheter?

If you are going to recommend giving intraperitoneal therapy, what therapy are you going to recommend?

DR. SWANSON: I was wondering if the GYN oncologists and oncologists could work with the nephrologists or the people that give peritoneal therapy on a regular basis to learn how to do it, and set up a program of giving it and kind of collaborate with another discipline. Like I said, it is sort of a stupid question but just as an outsider I was going to ask.

DR. ARMSTRONG: I am probably old enough to remember that it was originally the oncologists who sort of taught the nephrologists about intraperitoneal delivery.

It was being used for treatment of cancer before it was used for treatment -- as a dialysis methodology. So, if you find some folks who are old enough, you will probably find people who can do this.

I mean, it is not rocket science. It is a matter of just training people how to do it, training your staff how to troubleshoot.

I will say that we have not had trouble with reimbursement either. With regard to, Maurie, your issue about sort of the financial issues, we had several patients who came to us actually from this area, up to Hopkins , to get IP therapy.

The medical oncologists here, who now were not seeing those patients, asked us to come down. We did some presentations, had nurses talk, and the medical oncologists in this area, the two pretty large groups, are now giving IP therapy.

I think there is an incentive to be able to keep these patients in practice, that it is not just GYN oncologists, medical oncologists, if people want to keep treating these patients, they are able to do it with the proper incentive, which is that they want to keep patients and treat patients.

DR. OZOLS: Those of you who use intraperitoneal chemotherapy, I would just like to know what dose do you use? What is your schedule and what are the doses that you use? What trial do you use those doses?

DR. ARMSTRONG: We used GOG-172 protocol. We have a low threshold for dropping the cisplatinum dose for patients early on.

We try to use Joan Walker's guidelines for who might have trouble with IP catheters, and that helps us with timing of catheter placement. We really haven't had trouble getting patients through six cycles, recognizing what toxicities to look for, and to try and be proactive about doing modifications.

DR. AGHAJANIAN: 172 is where the big advantage is shown. That is what we do. Again, a big key is a low threshold to go from 100 to 75 on the platinum dose, to prevent the more severe side effects.

DR. ARMSTRONG: Mike, do you want to talk about your program in Boston , the weekly IP Taxol trials that you are doing?

DR. SEIDEN: We have not yet adopted it as an off-protocol standard, but our patients who are optimally cytoreduced are encouraged to enter an all IP Taxol carboplatinum trial, where the Taxol is delivered weekly at 70 milligrams per meter square, and the carbo is delivered Q three weeks, and you see a five.

We have been checking systemic PKs, both at cycle one and cycle six, to see if transfusion or pharmacokinetic profiles change after you pour in multiple cycles of chemotherapy.

It is still early. We don't have that many patients who have gotten through cycle six yet, but there may be some changes in the PK profiles between the first cycle, and that might be ready for ASCO. It is definitely a bit of a learning experience.

DR. MANNEL: I just put in a couple of comments, what the GOG ovarian committee is doing with this. At the current time, for advanced-stage ovarian cancer, who are optimally debulked, the protocol that is in development is an intraperitoneal protocol.

One of the issues that we are working with is toxicity. So, the trial is designed to come up with intraperitoneal regimens which may have a more accessible toxicity profile. That toxicity is independent of the catheter placement. That is a whole different issue.

The other area which I think is important for us to remember is that GOG is also, in the phase I study group, has an intraperitoneal queue.

So, there is a fair amount of work being done right now at the Cooperative Group level to try to do both, getting the most optimal regimen of existing drugs, and then moving forward some of the novel agents. So, both of those ideas are being addressed.

The hard part is that fundamentally I would go back to what Dr. Bookman said. It is very difficult to know where the therapeutic advantage comes from at the current time.

I think an analysis of 172 data will be interesting, in that there are probably those that didn't get but one cycle versus those that got six cycles. There probably wasn't a whole lot of difference in their therapeutic benefit. So, it raises the question of where the therapeutic benefit is coming.

DR. ARMSTRONG: Keiichi has probably got more experience with intraperitoneal carboplatinums than anybody else in this room. Maybe you could talk about that as well as the GOG phase I trial.

DR. FUJIWARA: As many people said, there are too many questions to be asked for the IP drugs. The main issue we have had for many years is what is the least toxic regimen?

We found that the IP carbo is quite feasible. The catheter problem has been very less, and when we published our data of 165 patients who had IP carbo-based chemotherapy, the number of cycles was five.

At that time, we did not combine any IP Taxol. So, it was single agent IP carbo versus, at that time, it was IP tigophosphamide, but we are now collecting more data using IP Taxol. So, we should have that data analyzed in a couple of months.

DR. BOOKMAN: You know, Dr. Markman and others have made some very pointed comments about how these data are being interpreted and how we are going to move on.

I don't want to respond to the members, the participants in the meeting today, but I think we do understand that this is important data, and that is why we are doing pilot studies and trying to look at toxicity and feasibility and make this something that is more appropriate for routine clinical practice but, at the same time, try to understand how to make it better.

You know, we have made mistakes in the past. There were countless efforts spent to evaluate things like dose intensity of platinum intravenously in ovarian cancer and other settings, that did not pan out to improve clinical outcomes.

One could argue that it made clinical outcomes worse because of serious hematologic and non-hematologic toxicities that patients had to endure because our hypothesis was not correct.

I think that we need to go forward. These are important data, but we ought to really try to learn as to where the advantage truly lies.

DR. HOWELL: There is really a terrific translational opportunity here. In the days that Jerry was talking about, when we first started measuring platinum, we had atomic absorption spectroscopy. It wasn't very sensitive.

Now we have ICPMS technology, which has parts per billion sensitivity. So, we can actually specifically address the question of how much platinum is getting to the tumor DNA in patients who receive intravenous cisplatinum versus intraperitoneal cisplatinum or carboplatinum. It doesn't matter.

So, that is an addressable -- it is complicated, because you have to get tumor, but it is an addressable question now, which we couldn't have addressed even a decade ago.

MS. BUTLER: I think, from listening to this debate, you may be able to see why the advocacy community has not adopted a clear position on this. It doesn't seem like it is ready for prime time yet.

As always, if we have one message, that message is, hurry. Is there a plan in place, or a series of plans in place, to get to some kind of reasonable conclusion about IP therapy and, if so, what kind of timeline are we talking about here?

It seems that some major institutions are adopting it as standards of care. Others roll their eyes and snicker. Where are we here?

DR. COUKOS: I just wanted to make a comment on the mechanism. So, in effect, if we don't know exactly how it works, that shouldn't deter us from trying it more?

I don't know that we know exactly why IP chemotherapy works or doesn't, but to answer a previous comment that it is very hard to interpret this, it is actually not that hard, I think.

We have an IP catheter and easy access to the IP environment, and there is today technology where we can analyze, at the proteomic level, a panel of cytokines at high throughput.

So, some of these questions can be answered, I think, very quickly if the cytokine environment to the peritoneal cavity is changed with the IP therapy.

Of course, lessons can be learned from phase II trials, where IP cytokine therapy has worked in preventing cancer. We do know that, or it has synergized with chemotherapy.

DR. SEIDEN: George, just to answer that question, getting back to some engineering issues, we participated with M.D. Anderson in an IP IL-12 study, and now are doing this current IP chemotherapy study.

We are very interested in looking at this. There is an extraordinarily tricky engineering aspect, and that is, you pour in a quart of peritoneal fluid, IV fluid, with chemotherapy and, 10 minutes later, it is very hard to get any good measurements.

Then the issue becomes, okay, well, I want to sample it. You can get some out by pouring more saline in, but then you have the issue that you have diluted.

DR. THOMAS: I would just like to make a comment before we let Ted actually have the last word. As a non-medical oncologist and as someone who doesn't treat advanced ovarian cancer, I think I would like to hear that, set in place with the clinical announcement from the NCI about the benefits of this regimen, are some very clear educational paragraphs to guide people from Deb's experience, about how to appropriately and rapidly dose reduce.

I think one of the reasons it is not prime time, aside from the catheter issue, is the concern that only 42 percent of patients could actually get the doses that were described in this protocol, and that people who are experts in this field know how to keep people safe by dose reduction.

So, if we are going to promote as a group that this regimen be the accepted regimen to start with, as a standard of care, then I personally would like to see, for our patients, very good educational guidelines as to how to protect the patient's safety, and maybe Ted can help us with understanding what the announcement will say and how it will help to educate.

Maybe the disks, CDs, that are passed out and sent out to everybody that is going to do this, to guide them properly, I think we need a big information sharing program.

DR. TRIMBLE: Thank you for that introduction, Gillian. When the data, the survival data from GOG-172, became available at the GOG meeting in January, we then made a decision to start the process to consider an NCI clinical announcement, which we do infrequently, but we do on occasion when there is a new trial or a body of evidence from a series of trials suggesting that we do need to think about changing clinical practice, and making information more available as widely as possible.

According to our guidelines, we convened an independent panel, appointed by NCI, by GOG, by SWOG and by URTC, incorporating advocates, some of whom are here.

We reviewed the data from the three trials and concluded that it was appropriate for NCI to develop a clinical announcement that would be timed to come out at the same time as the publication of the manuscripts from GOG-172.

Now, these include both primary manuscripts, of whom the first author is Deb Armstrong. There are secondary manuscripts by Joan Walker focusing on catheter outcomes.

It was critical that that data be available simultaneously with the clinical announcement, so that doctors could have the opportunity to review all the data on GOG-172, the data obviously from the SWOG/GOG trial, and the prior GOG trial already in the literature.

We are developing -- we will need to develop -- a series of informational packages on IP therapy that would be appropriate for use by medical oncologists, gynecologic oncologists, surgical oncologists, nurses and patients, patient advocates.

The message is, among the messages are, first, the importance of effective surgical cytoreduction, because we all know that intraperitoneal therapy appears to have a big benefit only in those patients who are optimally cytoreduced.

We also know that there are patients who do not have opportunity to undergo effective surgical cytoreduction. So, we hope that this announcement will be an opportunity to focus again on the opportunity of primary surgery for the treatment of advanced ovarian cancer.

The second message is that there is a marked improvement for survival associated with the administration of some of the chemotherapy by an intraperitoneal route.

We think it is critical that doctors and patients and their families know this information. We are not saying that every patient has to get IP therapy. What we are saying is that this should be discussed in the initial consultation for every patient.

Certainly there are going to be patients for whom intraperitoneal therapy is not indicated, and certainly the doctor and the patient will need to discuss the relative benefits versus the relative toxicity.

Nonetheless, the most recent trial showed a 17-month improvement in overall survival, which is comparable to what we saw with the introduction of Taxol and with the introduction of platinum.

We think it is critical that patients, their families, and their doctors know and discuss this information.

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