SLIDES & TRANSCRIPTS
Friday, December 13, 2002

Radical Nephrectomy with Mets: Con

Robert Dreicer, M.D.

I'll begin with a just a couple of brief introductory issues. Historically, nephrectomy for metastatic renal cell carcinoma used for management of pain, uncontrolled bleeding, and to decrease symptoms created by the paraneoplastic syndrome. And we know that we could do this well in the modern era without this approach.

People also talked about the role of nephrectomy in regression of metastatic disease. We now recognize that this sort of "up front, a priori" reason for nephrectomy is no longer valid.

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Now, the trials have been amply described, and I'm not going to go through them again, other than to point out some of the issues that are relevant as we try to translate this quality science into how we take care of patients every day. You have seen this data, and I didn't have the advantage of the meta-analysis, so there is no question that survival is improved, albeit modestly.

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The response rates in both trials, irrespective of whether or not there were differences, were very modest compared to objective response rates seen with biologics. Most folks quote 15 percent response rates to patients with metastatic disease treated with IL-2 or interferon.

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Approximately two-thirds of the patients in the SWOG trial had lung metastases only, which is a very important prognostic feature that we all recognize. And the imbalance was discussed, although the SWOG statisticians may find that it's not important irrespective of the issue, what it does tell us is that performance status does matter. There is no question here, and hammering on this point, we will come back to it.

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There is no question here, and hammering on this point, we will come back to it.

This information in terms of how this gets applied into clinical practice cannot be underemphasized. Because randomized clinical trials are done carefully, with very strict control of patient entry, patients with relatively small volume of metastatic disease and good performance status are included. So the question that we have to ponder is, "is that the patient population that is in the real world, that comes to the urologist, who is told he or she needs a nephrectomy?"

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Patient selection issues, even in clinical trials, are relevant. And as Dr. Flanigan pointed out, in the EORTC trial, there was a subset of patients who were taken to surgery, who did not receive immunotherapy, and ultimately that's also a very critical issue. The difference between the SWOG trial and the EORTC trial suggests that in certain hands, who you take to surgery, if you are going to take a patient to surgery who is not destined to get biologics or other systemic therapies, there again is no rationale to take that patient to surgery.

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So can they get through the surgery well enough to get to immunotherapy? Again, in the SWOG trial there was very good evidence that that could be done by carefully selecting patients. And obviously, as we move into an era where laparoscopic procedures or hand assisted robotics become more widely utilized, at least in some academic centers, the ability to get a patient through surgery onto to systemic therapy, that time interval would theoretically shorten.

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Now, there are various non-randomized studies that suggest that upward of anywhere from 40 to 77 percent of patients who underwent nephrectomy ultimately didn't receive immunotherapy. Studies that carefully select patients, meaning exclusion of liver and bone metastases, making sure that there are no brain metastases, patients who have clear cell histologies have a much higher likelihood of ultimately going on to receive biologics.

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Again, we understand that based on the randomized trials presented, that cytoreductive surgery does not improve the objective response. It improves survival. Other non-randomized series reported response rates of anywhere from 13 to 39 percent.

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Now, some observations. We have clear evidence from two randomized trials of a modest survival advantage conferred by nephrectomy prior to interferon. Can we extrapolate this to other systemic therapies? Well, you saw a little bit of data about interleukin-2. I would argue that hopefully in ten years we are not going to be talking IL-2 and interferon. We have squeezed these things about as hard as we can, and it doesn't get any better than 15 percent.

So the question now is, "do novel molecules that will be entering into clinical trials -- Bevacizumab, anti-VEGF -- are THOSE kinds of molecules going to require cytoreductive nephrectomy for activity?" I don't think one could make an extrapolation to all drugs that we are going to give to patients. The likelihood is we are going to have to revisit this question as we become more effective at developing effective systemic therapies.

Given that the time-to-systemic therapy is important, at least based on the trials that we have to date, utilization of advanced techniques will be important, although again, perhaps not as widely available in the community as it is in academic centers.

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And here, I think, is the crux of my concern. As is the case with many developments both in oncology and other areas of medicine, a generalization of recommendations occurs quickly. It is I think a community standard now that nephrectomy for patients with metastatic disease is the standard. So the sooner you get your patient into the urologist to have their kidney removed, the better.

The vast majority of patients that are seen in the real world are not really good candidates for systemic therapies to begin with. So when we take performance status patients of 2, 2.5, and take those patients with liver metastases, and expect that they are going to have the same kind of outcomes that we saw in the randomized trials, I think obviously that is not likely to happen.

And we, as academicians or community leaders, need to basically be leaders in educating our colleagues. This is one of those major areas where urology and medical oncology need to communicate. This is something that should have a dialogue between the surgeon and the oncologist. Ask yourselves, "is this the kind of patient that fits the criteria based on the evidence that we know, that this patient is going to benefit from being taken to surgery?"

I think that in general, for the majority of patients who present in the real world, cytoreductive nephrectomy may not necessarily be the appropriate therapy, and should not automatically be considered the standard of care.

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Patient selection, including those with optimal performance status, clear cell histology, because remember, biologics aren't particular effective in other subtypes of renal cell carcinoma, and therefore taking a patient to nephrectomy to give them a therapy that is not going to be effective, probably is not useful.

Excluding patients with occult CNS metastases I think are prerequisites for patients to have surgery, if they are going to have their intended utility. As one of my great mentors, the late Paul Corbone told me many times, the treatment should not be worse than the disease.

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Thank you.

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