Urologic Oncology

SLIDES & TRANSCRIPTS
Friday, December 13, 2002

Radical Nephrectomy with Mets: Pro

Robert Flanigan, M.D.

Slide 1:

Well, thank you, David, and hello everyone. David has already given you the summary of my talk, so I'll just go ahead and elaborate on some of the details.

The last time I spoke to this group, we had just completed the analysis of our SWOG protocol, and of course at the same, the EORTC was presenting their protocol, which has been developed from our specific protocol, and adopted. So it was a very precise copy of our protocol, with the same kinds of eligibility requirements.

Slide 2:

So what I want to do with you today is share the beginnings of the meta-analysis of these two trials, which were undertaken between the two groups. And then I also want to provide some single institution data, which looks at different immunotherapeutic agents in this subject.

Slide 3:

As I mentioned before, these trials were identical. In both trials the patients were randomized to nephrectomy, followed by interferon, versus interferon alone. And therefore, they asked the question, does cytoreductive nephrectomy have a role in this group of patients?

Slide 4:

The eligibility again, was identical, and could include any patients with nodal disease, but all of them had to have distant metastatic disease. They had to be amendable to surgical extirpation, and they could have thrombus in the inferior cava up to the level of the hepatic veins, but not above. They had to have performance status of 0 or 1, no prior chemotherapy, hormonal therapy, radiation therapy, or biologic response modification therapy.

Slide 5:

They all had to have a biopsy of either their primary tumor or the metastatic site with presumed renal cell cancer before being eligible. As well, they had to have normal liver function, renal function and had to be free of any of other malignancy for at least five years.

Slide 6:

The nephrectomy could be accomplished by any technique that the surgeon wished, although the ground rules were that (i) they had to remove the kidney outside of Gerota's fascia with early control of the vessels; and (ii) the nephrectomy had to occur within four weeks of registration. Lymphadenectomy was not required, but the surgeon had to note whether or not he or she had accomplished the lymphadenectomy, and whether there were lymph nodes present or absent.

Slide 7:

The interferon used was the Schering-Plough product in both studies, and was given at 5 million units per meter square, three times a week until progression occurred with an induction cycle, and also a standard adjustment for toxicity.

Slide 8:

The endpoints that both trials looked at were primarily survival, and secondarily clinical response.

Slide 9:

Statistical analysis was powered to detect a 50 percent difference in survival (power 0.85), and also a 15-30 percent difference in response rate (power of 0.85).

Slide 10:

These are the results when you combine both of the trials together. The SWOG trial was larger, 246 patients, but the two trials together produced 331 patients who were randomized. Of those, 7 or 2.1 percent were classified as ineligible, because the needle biopsy or whatever biopsy had been performed was incorrect subsequently at the time of nephrectomy.

Eighteen of the 181 patients in the nephrectomy arm, 11 percent, did not receive nephrectomy, and 3 of the 163 patients in the interferon-only arm did not receive interferon. This was an "intent to treat" trial.

Slide 11:

The eligibility criteria are shown here. And you can see that the only area where there was a difference in eligibility was an area of the performance status, with the larger number of the patients in the non-surgery group being at performance status 1, as opposed to 0.

Slide 12:

If you look at the combined overall survival of the two groups, with no surgery at 7.8 months, with surgery, 12.6 months, highly statistically significant. A 61 percent increase in survivorship with the surgery arm.

Slide 13:

If you look at it diagrammatically, you can see in the red, the surgery patients; in the yellow, the non-surgery patients. Obviously, there is a difference that one can see over time. And the other striking difference I think is in the long-term follow-up; almost uniformly the only patients alive in the long-term were those who had had a nephrectomy.

Slide 14:

If you broke this down in SWOG -- this is not a part of the multivariate analysis yet, we are still working on this -- in SWOG by the various different pre-stratification variables that we have looked at. You have seen this data presented before, but clearly, performance status is important. But in each level of performance status, there is roughly a 50 percent increase in survival in the nephrectomy arm.

Slide 15:

The same thing is true with site of metastasis. You look at patients who have lung only metastasis, who made up 67 percent of the patients in the SWOG trial. Again, roughly a 50 percent increase in survivorship, but clearly a better group of patients than those who did not have lung only metastases.

Slide 16:

And again, disease measurability. Again, many times reflecting some degree of lung metastases, which are more easily measurable. Almost 80 percent of the patients had measurable disease, with an increase of 50 percent in survivorship in these groups also.

Slide 17:

If you combine the one-year actual survivorship in the two groups, you can see that the chance of a patient living for one year without stratification is roughly 50 percent in the surgery arm, and about 1 in 3 in the non-surgery arm. And you can also see that the various different pre-stratification variables play an important role in addition.

Slide 18:

So in summary, in regard to the combination of these two trials, the average median survivorship for the interferon-only arm was 7.8 months, as compared to 12.6 months in the nephrectomy-plus-interferon arm. And it did represent a 61.5 percent increase. And there was an increased survivorship advantage maintained across all the stratification variables, which were assessed pre-trial.

Slide 19:

Responses were different between the two groups. This is a summary of the responses as seen in the two groups added together. In the nephrectomy arm there was a 12.5 percent objective response rate; in the non-nephrectomy arm, a 9 percent objective response rate. If all patients were included, not just the patients who had measurable disease, the response rates were lower, 6.7 percent in nephrectomy arm, and 4.9 percent in non-nephrectomy arm.

Slide 20:

When I presented this work last time, we heard a lot of discussion. One of the questions which was asked by the audience was: "What is the effect of response in this group of patients?" I did go back to our SWOG statistical office and looked at all the patients individually. In our SWOG series, if a patient was an objective responder, they had a median survivorship of 2.9 years, as compared to 10.2 months for those patients who were not responders.

If patients developed stable disease by SWOG criteria, they had an overall median survivorship of 2.1 years, which was 2.9 years in the nephrectomy arm, and 1.8 years in the non-nephrectomy arm.

Slide 21:

As we had known before, adding the trials together, surgical complications are much less prominent than we thought they might be. Eighty percent of the patients in both trials had no complications, and major complications occurred in only a small percentage of the patients.

Slide 22:

Also, complications of interferon were rare. One patient died of cardiovascular toxicity in the interferon-only arm. And grade IV toxicity occurred in only 10 of the 296 patients (3.4%) who received interferon in both arms of the study.

Slide 23:

Another question that was asked the last time was the quality of life. And we had no quality of life measurement as a part of the studies originally. But I did go back and look at the SWOG data. The mean time of hospitalization for nephrectomy arm patients was 8.2 days. This trial had been going on for quite some time, many of you remember, so it isn't probably as easily compared to the short periods of time we keep people in the hospital today.

And the time to initiation of interferon therapy after surgery was a little bit less than 20 days.

Slide 24:

So the arguments against cytoreductive nephrectomy are at least three. Mortality and morbidity of surgery is too high. Patients will not be able to proceed to biologic agents. And most patients do not respond to the biologic therapy, so why not preserve it for those who do? These two trials, I think address the first two issues.

Slide 25:

In terms of mortality and morbidity, there were only two deaths in the combined series, or 1.5 percent in the surgery arm. And I mentioned before the complications were acceptable in this group of patients.

Slide 26:

In patients not able to respond to biologic therapy, histologic series are very widely variant. Up to 50 percent of patients, depending on (i) which immunotherapeutic treatment was to be given, and (ii) the pre-operative evaluation of the patients. In our study, we found a large number of patients who were able to go onto biologic therapy. In fact, only 6.2 percent did not proceed to interferon therapy, as you can see. There was a difference between the SWOG and the EORTC trials in this regard.

Slide 27:

What are the possible limitations of this trial? First of all, the overall survival advantage is certainly not what we would like it to be, even though it represents a 61.5 percent increase. There was a possible randomization imbalance in terms of performance status, but our statisticians in SWOG at least tell us that this is probably not a valid criticism of the trial, given the fact that there is a survival advantage across all of the pre-stratification variables.

Slide 28:

These two trials are the first prospective trials of cytoreductive nephrectomy in this era. They do show a clear-cut survival advantage. The SWOG trial data that we have so far shows, and hopefully also in the meta-analysis, an enhancement of survival across all the pre-stratification variables.

Additionally, there have been other studies. I'm only going to show you one today, which I had the opportunity to participate in with our UCLA colleagues, which was actually presented to the AUA meeting last year.

Slide 29:

At UCLA they looked at 89 patients who were chosen to be able to meet the entrance criteria to the SWOG trial. They were treated with cytoreductive nephrectomy and IL-2. The overall survivorship was 16.7 months, or a 30 percent increase over those seen in the SWOG nephrectomy-plus-interferon arm.

Survival at five years was 19.6 percent, compared to 10 percent in the SWOG nephrectomy-plus-interferon arm. This suggests, perhaps, that greater durability of responses with cytoreduction might be accomplished with more aggressive, state-of-the-art cytokine therapy. Of course, the validity of these conclusions are compromised by the fact that this is a historical comparison.

Slide 30:

This slide shows you percent survival, comparing the UCLA series of well-matched patients in red, to the surgery-plus-interferon in yellow from the SWOG trial, and the green, interferon-only.

Slide 31:

Again, I showed this slide last time, and I will use it again. Is this the evidence for a new algorithm in the management of metastatic renal cancer? I think it is, probably yes, but again, the physician must be very cognizant that other factors, such as performance status. As well, the overall status of the patient may alter the survivorship advantage. Therefore, a great degree of patient selection must be entertained.

Thanks very much.