So I think cytoreductive nephrectomy for renal cell carcinoma is one of the most controversial issues in GU oncology right now. The reason being that the role of cytoreductive nephrectomy was established for metastatic renal cell carcinoma. Patients presented with upfront metastatic disease in the cytokine era, where we didn't really have very effective systemic therapies for patients with metastatic RCC. Now, after that, overall survival benefit was established at that time. The question that begs itself is, now that we have much more effective systemic therapies, such as targeted therapies and more recently, immune checkpoint inhibitors, is there still a role for cytoreductive nephrectomy for metastatic RCC?
Now, some of the response to that question came from large retrospective studies, that had found that cytoreductive nephrectomy was still associated with an overall survival benefit. Now, these studies are retrospective, so although they were very diligent in controlling for confounding factors, these were not randomized controlled trials. So this is why I think the CARMENA trial, in particular, was very important. The CARMENA trial randomized patients to either sunitinib alone, or sunitinib plus cytoreductive nephrectomy for metastatic RCC. What that trial found was that sunitinib alone was non-inferior to cytoreductive nephrectomy plus sunitinib.
Now, this is a randomized controlled trial. It is the gold standard. But there is even with randomized controlled trials, there are some caveats. For instance, the study had mostly poor to intermediate risk disease. The study had patients with relatively high metastatic burden, which in clinical practice, many would argue would not be referred to a cytoreductive nephrectomy. And also, even in that study, the patients that were lower risk disease tended to benefit from cytoreductive nephrectomy. This is a subgroup analysis presented recently.
So with all that in mind, the question that we tried to ask is, now that we have even more effective therapies, such as immune checkpoint inhibitors, since cytoreductive nephrectomy in practice is still being performed, is there still a role, is there still an overall survival benefit to cytoreductive nephrectomy in the immune checkpoint inhibitor era? To answer this question, we looked at the IMDC data set, which is a large retrospective consecutive series of patients with metastatic RCC. We studied with more than 11,000 patients with metastatic RCC. After moving the patients that had localized disease, or the patients that had missing data, we ended up with around 4,500 patients, divided into a first line targeted therapy treated group, and a first line immune checkpoint inhibitor group. Each of these then divided into a cytoreductive nephrectomy or no cytoreductive nephrectomy group.
The first question we asked was, what is the profile of patients getting cytoreductive nephrectomy? And we found that patients getting cytoreductive nephrectomy were younger, had lower risk disease by INDC criteria, and had less bone, brain, and liver metastases, which are classically associated with a poor prognosis.
The next question we asked, and I think the most important one, was, is there still an overall survival benefit in the immune checkpoint era? And we compared that to the data in the target therapy era. What we found was that the benefit from cytoreductive nephrectomy in the immune checkpoint inhibitor treated patients-- the first line immune checkpoint inhibitor treated patients-- seemed to be consistent with targeted therapy data. Meaning that there was an overall survival benefit, either univariably, or after very diligently correcting for confounding factors using a classical multi-variable model approach or an IPTW, which is a propensity score based method approach, to adjust for confounding factors. I think crucially, the extent of benefit associated with cytoreductive nephrectomy seemed consistent across the immune checkpoint inhibitor target therapy era.
So in conclusion, using this large retrospective data set, we found that patients in the immune checkpoint inhibitor era seemed to still derive a benefit from cytoreductive nephrectomy. We tried to be very diligent and correct for confounding factors, but there are always limitations to these retrospective analyses. But in the meantime, I believe that, in practice, patients could potentially still receive cytoreductive nephrectomy even though we have these more effective systemic therapies. But these patients should be very selective. They should be good risk. They should have low metastatic burden. And I think the overall evidence so far suggests this.
So while we wait for more randomized controlled trials, such as the NORDIC-SUN trial, the PROBE trial, or the CYTOSHRINK trial, that are all ongoing and will report in a couple of years, I think the evidence suggests that there is potentially still a role for cytoreductive nephrectomy in the immune checkpoint inhibitor era.