DR. WOOD: If there is no difference in the objective response, then why did the patients that get the nephrectomy do better?

DR. FLANIGAN: Well, I guess the simple answer to that question is we don't know. There are many different theories that have been espoused, including the fact that cytokine released from the primary tumor may cause decreased immunologic status, and other nutritional factors in a patient.

We actually were intrigued by a group from the University of New Mexico who contacted us to look at our SWOG data about the issue of milieu of the remaining tumor, in light of their work on mathematical models that have suggested that the patient's acid-base metabolism may actually have an impact on how their metastases grow.

And they looked at our SWOG data in regards to chances in creatinine and BUN, and showed in fact -- and it was just published recently -- that patients who had a more dramatic change in BUN and creatinine related to their nephrectomy, had a better survival result in our study. So there are many different theories. I don't think we know the answer to it at this point.

DR. WOOD: I'm hard pressed, Rob, can you think of in medical oncology, another situation where resection of the primary tumor -- I think there are some - can improve the results of the overall survival of patients without changing the objective response rates?

DR. DREICER: I think, as a general principle, probably not. Objective response rates in diseases for which cytotoxic therapies are important are usually thought to be a prerequisite for improvement and survival. Renal cell is not your average epithelial tumor, and we all recognize that there are various "evil humors" in that disease that we don't have the faintest clue about. In and of itself, from a biologic principle, I don't have any problem with this phenomenon. This was a randomized trial. The evidence is there. There is benefit. The fact that we don't understand it just means that we've got some work to do.

DR. WOOD: I had a series of questions, which we can adhere to or not. If resection of the primary tumor is beneficial, who should undergo nephrectomy? Dave Swanson, do you believe that in the future all patients with metatstatic renal cell should undergo nephrectomy, particularly if it's in a clinical trial? And then, should all future clinical trials with metastatic renal cell carcinoma, evaluating some sort of a biological, require that you have to have your kidney removed for trial eligibility, because otherwise you are not following the current standard?

DR. SWANSON: I think that's a very dangerous place to go and Rob expressed many of my feelings on that. I think that he joins a very select list, a short list of medical oncologists who aren't pushing for initial cytoreductive nephrectomy. The truth of the matter is that most of the medical oncologists I know prefer it. Many patients, if not most, prefer it. And I think that, as he mentioned, in this day and age it can be done safely in many patients.

But what has happened is that those observations have been extended to a flat out rule, which is not very flexible. And when people write editorials and say 'this is the standard of care,' then there are people out there acting reflexively, instead of thinking about it and applying it only to appropriate patients, both on the basis of where their metastases are, and the extent of the metastases, their general health, and the grade of the tumor as well.

We have some data that Joel Slaten put together that showed that the high grade tumors, grade four and sarcomatoids had such a high death rate at six months, and were less likely to be palliated if symptomatic, that it doesn't make sense to press forward with the cytoreductive nephrectomy in those patients.

DR. FLANIGAN: I really think this is probably, as Rob mentioned before, the place where we have to work together in a multidisciplinary approach. And I think it is silly for a urologist to make these decisions in exclusion of a medical oncologist that they work with all the time, and would be treating this patient together.

And I would say, obviously, since we published this paper, and we have had a lot of patients that have come to our institution for this procedure, but as Rob pointed out, there are a lot of patients in whom we do not recommend this to go forward. And we are able to do that by presenting what we think is an honest appraisal of what the likelihood of response is going to be, given their performance status, et cetera.
And also involving at the same time, at the same visit, our medical oncology colleagues who offer another way to proceed, which is with immunologic therapy to begin with. So that's the way we approach it.

DR. WOOD: Right. I would like to invite some questions from the audience.

DR. THOMPSON: Can I interrupt real quick? I didn't hear an answer to your question. (question interrupted…)

DR. LINEHAN: I was just going to say, I would like to know if anyone on the panel knows any data to support that statement editorial that this is the gold standard? I'm not aware of any data that nephrectomy prolongs survival. Now, in the context of a trial with systemic therapy, with our medical oncologists, I can see that. But is there any data that nephrectomy on its own prolongs survival? I think it's a slippery slope. If we start saying that, I think many of our colleagues in the private sector, as we say, I think have gotten that message. And I think it's important for us to be thoughtful about it, number one.

Number two, has anyone of you all seen response -- we have not since 1984, in a patient with non-clear cell histology? We are getting ready to put that together. I wouldn't say that our experience says "non-clear cell histology does not respond".

But we have not seen response of anything other than clear cell, either with IL-2 based therapies at our place, or with Rick Childs allogeneic stem cell transplantation. I think he feels he doesn't have enough data on the non-clears to know. I'll let him speak for himself this afternoon.

But that's kind of our experience. Do other people have the same experience?

DR. FLANIGAN: We did break it down, and I looked at that. And it's not easy to get to that information easily, because number one, as we heard in the wonderful talk just before this panel, the pathology has changed so dramatically.

But if you look at just purely what I could glean from the records in SWOG, there were a couple of patients who were said to have papillary tumors, who did respond. Now, whether they really did, or whether they were incorrectly classified given our modern day classification, I don't know.

DR. WOOD: Ian, what about the clinical trials question? In these major cooperative groups, if there is IL-2, does nephrectomy need to participate in that trial? Do you need to have a nephrectomy first to then be able to say 'yes, this biological agent is better or worse'?

DR. THOMPSON: I don't profess to know the answer to that. It's very much of a slope, because if you are going to be enrolling strictly patients with performance status 0, then perhaps yes. But that's going to be the minority of patients that you really want to test new agents in.

So for the remainder of those patients with the higher performance status, if you look at a two-month survival advantage, and the potential down time that you get from the nephrectomy from that, is there really a substantial amount of improvement in that higher performance status group? And that's really the group of patients that you really want to test.

And then you get into the question, do you mandate a nephrectomy in performance status 0, and then not in 1 and up? Oh, slippery slope. So perhaps the statisticians might say 'stratify by nephrectomy'.

DR. WOOD: David?

DR. SWANSON: One thing, I might have preferred to save it as a final statement, but in case I don't get a chance, I think there is one caveat that the SWOG trial and the EORTC did not exclude the possibility that DELAYED nephrectomy after response to initial systemic therapy would be beneficial. And we are simply saying 'systemic therapy can be very successful, but is unlikely to remove all disease'? As well, historically, if you have a residual organ (primary kidney tumor) systemic therapy has not been as successful at treating the disease in the primary tumor.

DR. FLANIGAN: When we in SWOG looked at this, we came to the conclusion that we should include nephrectomy as a part of the trials. And I think one of the reasons the renal cell subcommittee suggested this was that, if you are going to try a new agent, and you probably going to be limited in terms of the number of patients you can analyze up front, as is the case in most of these trials (whether they be phase II or even phase III trials), isn't it better to get a group of patients who you think have the best likelihood of responding to the agent, and then optimize everything else in favor of that. And also, if you show a survival advantage in a group of patients who did not have nephrectomy, you have to go back a second time in my mind, and compare it to what would have been accomplished with what we believe is the best arm of our phase III trial. So that's the reason we came to that conclusion.

DR. FERDET: Yes, I would like to be a little bit provocative, and maybe it's my understanding the trial that is not correct, but in my view of this trial, the experimental arm was really 'does surgery improve survival'? And the constant was the interferon treatment. So my question is whether we have data other than 'surgery may improve survival in the good risk patients with metastases'; that is, do we have evidence that adding interferon does something?

DR. WOOD: Rob Dreicer, in your view, was interferon essentially water, and we really were looking at the effect of surgery alone? Or do you need -- the argument would be that you need to have nephrectomy PLUS interferon, and then you can test some other agent? That is, after all, the best arm.

Or, if urologists are well known to not do randomized clinical trials, and then if you do them, you don't believe them, is this one of those cases where we showed it, and now we are saying, well, yes, but maybe we don't really have to do that?

DR. DREICER: One of the most instructive trials ever done, in my mind, and which I bang my fellows with, is Marty Gleave and colleagues trial of gamma interferon in renal cell, in which the response rate in the control arm was higher than the objective response arm in the gamma interferon, including 3.3 percent complete responders.
I think what that tells us is kidney cancer is a really strange disease, and you've got to do controlled trials. Now, I don't know the answers. Interferon has an objective response rate. Eight million patients later we know. It's modest, but it's real. Now, how much of that 15 percent objective response rate would be just patient selection issues? If you did a no-treatment vs. interferon arm, you are going to find the percent.
I think the trials that we have today probably are a real advance. It's a very modest advance. It tells us something about the biology of the disease that has to be explored. But it also may be unique to the biologic that was chosen along with surgery.

Again, I come back to this. Whether this will hold up when we start using, hopefully, more active agents of a totally different class, I don't know the answer to that. I think we are going to have to retest that question, because this is not a small issue.

DR. WOOD: Dr. Block.

DR. BLOCK: To speculate, what would happen if we treated patients with interleukin or other biological response modifiers first, and then compared nephrectomy in those that responded with nephrectomy in those that didn't respond(?)?

DR. DREICER: As you know, there have been several institutions around the country that have historically sort of internally done that for many years without testing it prospectively. It would be a much longer trial, and much harder to do, needless to say.

DR. WOOD: I don't want to jump on the next section, which is the treatment of advanced disease, but I do think Ian brought up a good point. I would like to talk to him a little bit. Should we start getting this generalized out to the community? Again, we are being inundated like most other people with these huge tumors. Bringing in the factor of the co-morbidity, and the relatively small improvement in survival, should this approach be disseminated to the community? I would like to go down the panel with this as the last question. We'll start with Bob, because I do want David Swanson to have the last word. Okay, let's start with Dave.

Which patient with metastatic disease should get a nephrectomy? Who should it be? Give us some practical guidelines - small tumors? Symptomatic tumors?

DR. SWANSON: I think the question has largely been rendered moot. I think that if you skim off the sickest 15-20 percent in terms of performance status, co-morbidities, tumor burden, where the sites are, etc., you can get the other patients safely through the surgery and started on systemic therapy in a timely fashion.
I think I resent most of all the fact that this is being labeled as 'standard of care', but I think from a practical viewpoint, there is little reason not to do it if there is not going to be excessive morbidity.

DR. THOMPSON: I just use the eligibility criteria for the trial.

DR. DREICER: I think that's reasonable. Good performance status, clear cell histology, which is not an eligibility issue in that trial, and low volume metastatic disease, preferably in the lung and other soft tissue.

DR. WOOD: Should interferon be given also -- Bob, I would like you to address that -- or can we use any biologics that we want?

DR. THOMPSON: Can I ask a question of Bob? Do you routinely biopsy your patients prior to performing a nephrectomy?

DR. DREICER: No, that's why your issue is very relevant, obviously.

DR. FLANIGAN: The one neat thing that could happen if we could somehow put together another trial looking at this subject, which I hope we can, is that there are a lot of different potential predictors of response. There is one Japanese trial for example, that has looked at C-reactive protein, as we are hearing about in heart disease now. But also, in patients who were treated with cytoreductive nephrectomy, and finding that that (C-reactive protein) is a predictive test.

There are, I think, a lot of things we could learn and try to stratify patients who may respond better to cytoreductive nephrectomy. But until that time, I would have to say that we would go along with the eligibility requirements. I would not do this in somebody with a performance status of two, metastatic disease in every part of his or her body, which we see in the clinic, and so forth and so on. I don't think that's fair to the patient.

And I think the way we do that is the way I mentioned before, in close collaboration with our medical oncologists, and a very honest discussion about what the data is so far.

DR. WOOD: Do patients need to get interferon? We have kind of glossed over that again. But that was the combination, and as Rob Dreicer said, perhaps it is that combination? Do they need to get interferon also?

DR. FLANIGAN: I would like to see any future trials, phase III trials use the nephrectomy-plus-interferon as the control arm. If you are not using it as a trial, and you are for example, basing it on the historical evidence from the UCLA experience, I don't think they have to, no.

DR. WOOD: All right, if there are no further questions, Dr. Linehan -- oh, I'm sorry, please go ahead.

DR. JOHN MILNER: Just one thing that I failed to notice mentioned here is anything on quality of life in those additional median 4.8 months survival that you are getting. And I would just encourage any future studies to have that as an adjunct, as the quality of life in the patients; if they are all in wheelchairs with broken femurs, that might be something to consider.

And the other thing that I would just like to ask is that no one has mentioned anything about angioablation. And I understand that there are obviously a lot of collateral vessels that are significant. You are not going to kill all the tumor cells, but maybe angioablation as the most minimally invasive procedure could have some impact on the natural history of the disease. This might be worth looking at as well.

DR. FLANIGAN: One quick piece of information. When I reviewed all of the cases at the SWOG staff headquarters, when those patients died, at least according to the chart review, they died quickly. The progression was a rapid thing over a month's period of time, somewhere in that vicinity. So at least looking at it, although not scientifically I guess, you wouldn't get the impression that the vast majority of those patients were not functional up until a very short period of time before they died.

DR. WOOD: All right, thank you very much.
Dr. Linehan.

DR. LINEHAN: Thank you. Great session! Thank you. We are now going to have a break, which will be upstairs where the poster session is.

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